Special Considerations for Cardiovascular Diseases: Ventricular Assist Devices and Heart Transplantation

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Patients with advanced chronic heart failure (stage D, end stage) treated with maximal medical therapy, optimal lifestyle including regular exercise and healthy eating habits, and implantable cardiac defibrillator (ICD)/pacemaker therapy (cardiac resynchronization therapy) when indicated often have refractory symptoms, very limited exercise tolerance, and poor quality of life. One-year survival is ≤25% and is particularly dismal for patients with a peak volume of oxygen consumed per unit time (O₂) of ≤12 mL ∙ kg⁻¹ ∙ min⁻¹ (3,35). The purpose of this chapter is to describe two treatment options that allow patients with advanced chronic heart failure to function outside of the hospital: mechanical circulatory support with a left ventricular assist device (LVAD) and heart transplantation. In addition, responses to acute and chronic exercise for each treatment option for these patients are described.

Case Study 11-1

Mr. Case Study-HtTxp

The patient is a 46-year-old man with a 17-year history of familial nonischemic dilated cardiomyopathy that is managed medically. An ICD was inserted in 2011. Other pertinent medical history includes severe obesity with bariatric surgery in 2010, which resulted in a 100-lb (45 kg) weight loss, obstructive sleep apnea, cerebrovascular accident with complete resolution of symptoms, and left lower extremity deep vein thrombosis.

He recently became progressively more symptomatic with minimal physical activity (New York Heart Association class IV) and was hospitalized in his hometown and found to be in severe congestive heart failure (CHF) with frequent episodes of nonsustained ventricular tachycardia. Subsequently, he was transferred to the Mayo Clinic for a 42-day inpatient stay. The echocardiogram revealed severe left ventricular enlargement with an ejection fraction of 14%, generalized hypokinesis and increased filling pressure, moderate right ventricular enlargement, moderate-to-severe reduction in systolic function, and an elevated right ventricular systolic pressure of 51 mm Hg.

Aggressive diuresis was successful in improving symptoms to the point that he was able to perform a cardiopulmonary exercise test a week later with a peak O₂ of 7 mL ∙ kg⁻¹ ∙ min⁻¹, 19% of predicted for his age (Table 11.1). His heart catheterization revealed normal coronary arteries with evidence of moderate pulmonary hypertension with a mean pulmonary artery pressure of 42 mm Hg. An intra-aortic balloon pump was inserted to support cardiac output.

Table 11.1

Cardiopulmonary Exercise Test Data

Sequence of Cardiopulmonary Exercise Tests
	Pre-LVAD	85 Days after LVAD	105 Days after Transplant	363 Days after Transplant
Body weight (kg)	101.2	92.0	91.1	95.8
Rest HR (bpm)	88	83	107	111
Peak HR (bpm)	100	115	131	196
HR 1 min (bpm)	95	104	142	184
Rest SBP (mm Hg)	80	—	134	140
Peak SBP (mm Hg)	80	—	158	164
Peak O₂ (mL ∙ min⁻¹)	710	1160	1561	1821
Peak O₂ (mL ∙ kg⁻¹ ∙ min⁻¹)	7.0	12.6	17.2	18.9
% Predicted	19	34	47	53
Peak RER	1.16	1.12	1.27	1.39
E/CO₂ slope	38	30	37	31

HR 1 min, heart rate at 1 minute after peak exercise; SBP, systolic blood pressure; RER, respiratory exchange ratio; E/CO₂, minute volume/carbon dioxide production.

He was considered to be a candidate for heart transplantation, but because of concern for his immediate survival, he underwent surgery to remove the intra-aortic balloon pump and to install a continuous-flow LVAD as a bridge to transplant. Approximately 2 weeks after the operation, the patient developed abdominal pain and was found to have necrotic cholecystitis. A laparoscopic cholecystectomy was performed. A week later, he underwent separate catheter ablations for both symptomatic atrial fibrillation and symptomatic nonsustained ventricular tachycardia.

The patient returned to his hometown after discharge from the hospital and gradually increased walking duration to 30 minutes at a moderate pace most days of the week. He returned to the Mayo Clinic 2 months later for treatment of a LVAD drive-line infection. An echocardiogram at the time demonstrated partial recovery of left ventricular function with an ejection fraction to 37%. Peak O₂ measured with cardiopulmonary exercise testing had improved to 12.6 mL ∙ kg⁻¹ ∙ min⁻¹, 34% of predicted (see Table 11.1).

Five months after implantation of the LVAD, a suitable donor organ became available, and the patient underwent orthotopic heart transplantation as well as removal of the LVAD and ICD. Postoperative course was uncomplicated, and the physical medicine and rehabilitation health care providers worked with the patient to increase physical activity, beginning ambulation 24 hours postoperative when intubation was discontinued. The patient was discharged from the hospital 10 days after surgery. The transplant team consulted with the patient on a frequent basis after hospital discharge, and periodic right ventricular biopsies were performed with only two episodes of very mild acute rejection diagnosed in the first several months after the transplant. The patient was required to reside close to the hospital for the first 3 months after surgery to facilitate close monitoring by the transplant team. Selected prescribed medications included the following:

Immunosuppressants: mycophenolate mofetil, prednisone (with a gradual taper over time), and tacrolimus, which was transitioned to sirolimus a few months after transplantation

Cardiovascular medications: furosemide, amlodipine, pravastatin, sildenafil, and aspirin

The patient began outpatient cardiac rehabilitation (CR) 14 days after transplantation. Initial 6-minute walk distance was 338 m (1108 ft), 53% of his predicted. The initial estimated one repetition maximum (1-RM) for the leg press was 221 lb. He completed questionnaires for both depression and neuromuscular deficits, and both were negative. For the first 6 weeks of CR, the patient participated in seven supervised exercise sessions using the treadmill for aerobic exercise (gradual increase in duration to 30 min per session), free weights (biceps curl, triceps extension, shoulder press), and weight machines (leg press, leg curl, upright row), one to two sets of 8–15 slow repetitions per exercise, keeping the resistance for upper extremity exercises at ≤10 lb for the first 8 weeks after surgery to allow for sternal healing. The intensity for both aerobic and strength exercise was prescribed using ratings of perceived exertion (RPEs) of 12–14 on the 6–20 scale. Over the next 7 weeks, he performed more frequent exercise sessions, with a total of 23 supervised exercise sessions at completion of 3 months of outpatient CR.

At the end of outpatient CR, the estimated 1-RM for the leg press was 466 lb, and his cardiopulmonary exercise test demonstrated a peak O₂ of 17.2 mL ∙ kg⁻¹ ∙ min⁻¹, 47% of predicted (see Table 11.1). Repeat 6-minute walk distance was 541 m (1774 ft), 84% of his predicted distance. The patient was discharged to home by the transplant team and an exercise prescription was provided by CR staff: treadmill or outdoor walking, RPE 12–14, 30–45 minutes 5–6 days per week and strength training exercises as performed in rehabilitation, 2–3 days per week.

A year after transplantation, Mr. Case Study-HtTxp reported a favorable quality of life and was walking >30 minutes, three times weekly. A repeat cardiopulmonary exercise test demonstrated a peak O₂ of 18.9 mL ∙ kg⁻¹ ∙ min⁻¹, 53% of predicted (see Table 11.1).

Description, Prevalence, and Etiology

For patients with advanced heart failure, heart transplantation remains the gold standard therapy. However, there exists a substantial donor-organ shortage, and many patients are not candidates for transplantation due to comorbid conditions (37). LVAD therapy is an attractive option for maintaining patient viability while awaiting transplantation (LVAD as a bridge to transplant) or as permanent use for a patient not deemed suitable for transplantation (LVAD as destination therapy). LVAD therapy may also be used as a bridge to recovery in patients with the possibility of improvement in cardiac function or as a bridge to decision of treatment options in rapidly deteriorating patients (20). Approximately 2,400 LVADs were implanted in the United States in 2014 (20).

Left Ventricular Assist Devices

An LVAD is a battery-powered (external battery pack) pump surgically implanted in the upper abdomen (Fig. 11.1). Circulatory support is provided by pulling blood from the left ventricle and pumping it into the aorta. The current LVAD technology provides continuous blood flow and results in lower mortality than the previous pulsatile flow devices (37). There may be no palpable pulse due to absent pulsatile flow, and blood pressure (BP) may be difficult or impossible to measure using standard auscultatory techniques. BP can be measured using a Doppler probe but may represent the pressure at any point in the cardiac cycle and should not be considered the actual systolic, diastolic, or mean pressure (38). During exercise, for some patients with LVAD, it is difficult or impossible to detect BP even with Doppler. Continuous-flow LVADs unload the left ventricle and operate at a fixed speed which may be adjusted to optimize left ventricular unloading. Cardiac output is relatively fixed and changes little during exercise.

Cardiac output is normal at rest and is provided primarily by the LVAD; the aortic valve remains closed throughout the cardiac cycle in most patients. During exercise, there is variable contribution of the native left ventricle, and in the majority of patients, the aortic valve remains open during exercise (27). LVADs typically provide 66%–93% of the total cardiac output during exercise with the remaining portion of the cardiac output provided by the stroke volume of the native heart (1). The cardiac output is adequate for many usual physical activities. However, exercise cardiac output is subnormal, and exercise capacity is limited with peak O₂ averaging 12–18 mL ∙ kg⁻¹ ∙ min⁻¹ (27). Additional reasons for below normal exercise capacity include the persistent CHF-related abnormalities, such as chronotropic incompetence, skeletal myopathy, endothelial dysfunction, right ventricular dysfunction, and anemia.

One-year survival for patients using an LVAD as a bridge to transplant is 68% (41). One- and 2-year survivals for destination therapy are 75% and 62%, respectively (3). After implantation, there may be spontaneous improvement in exercise capacity, reduced symptoms, improved end-organ function, and improved appetite, but full benefit is not achieved for 12–26 weeks. In some patients, reverse left ventricle remodeling may occur resulting in partial normalization of left ventricle systolic function with a concomitant reduction in pulmonary congestion and dead space ventilation (recovery) (1,11,27). Older adult patients appear to derive less benefit than younger patients.

After implantation, patients continue to receive complicated medical care related to their CHF and multisystem dysfunction as well as LVAD-specific issues. Patients with LVAD require anticoagulant therapy with an attendant increased bleeding risk. These patients are also at increased risk for fluid imbalance, stroke, hemolysis, infection, arrhythmias, and right ventricular and multiorgan failure (1,37). CR programs are well positioned to assist these patients with their complex care and to provide medical surveillance (1). CR staff should work with the LVAD team at the institution that performed the implant regarding the specific device characteristics, such as proper driveline immobilization and care, device alarm settings, etc. An important consideration in a medical emergency involving a patient with LVAD is that cardiopulmonary resuscitation (CPR) should not be performed due to risk of dislodgement of the device.

Patients with LVAD may be challenging candidates for exercise training due to profound deconditioning, low cardiac output state, fatigue, and skeletal muscle weakness. After LVAD implantation, most patients have persistent functional limitations. Kerrigan et al. (16) reported an average peak O₂ 90 days postimplantation of only 12.9 ± 3.1 mL ∙ kg⁻¹ ∙ min⁻¹. The limited numbers of exercise training studies performed thus far have demonstrated that exercise training is safe; no major exercise-related adverse events have been reported. Some patients demonstrate an improved peak O₂ after training. Essentially, all patients improve submaximal exercise endurance (longer exercise time to fatigue at a fixed workload) (1). However, the long-term effects of exercise training have not been investigated.

Two recent randomized, controlled trials of exercise training after LVAD implantation merit discussion. Kerrigan and associates (15) randomized 27 patients, an average of 2.8 months after implantation, to either CR-supervised exercise training or usual care. Exercise training consisted of 18 sessions over 6 weeks and included treadmill or cycle exercise for 30 minutes initially at 60% of heart rate reserve (HRR), increasing to 80% of HRR. There were no significant changes in peak O₂ for the usual care group. The exercise group increased peak O₂ from 13.6 to 15.3 mL ∙ kg⁻¹ ∙ min⁻¹. Although strength training was not a component of the CR program, knee extension strength increased by 17% in the exercise group and did not change with usual care. Quality of life score and 6-minute walk distance increased more for the exercise group than for the usual care group. In 313 supervised exercise sessions, one syncopal episode occurred, although a cardiovascular etiology was not determined.

Laoutaris and associates (25) randomized 15 LVAD or biventricular assist device (LVAD + right ventricular assist device [RVAD]) recipients to either home-based exercise training and inspiratory muscle training or usual care. Both groups were encouraged to walk 30–45 minutes daily. The home exercise training took place on either cycle ergometers or treadmills with a goal of 45 minutes, three to five times per week, at RPE levels of 12–14 on the Borg 6–20 scale. Inspiratory muscle training took place twice weekly at the hospital at an intensity of 60% of maximal inspiratory strength to exhaustion. Peak O₂ did not change for the usual care group but did increase from 16.8 to 19.3 mL ∙ kg⁻¹ ∙ min⁻¹ in the exercise group. Improvements in the quality of life score, 6-minute walk distance (65 m vs. 18 m), and the minute volume/carbon dioxide production (E/CO₂) slope were greater for the exercise group than the usual care group.

Early mobilization, including walking with and without supervision, may begin within 1 week of surgery. Patients may begin outpatient exercise training 2–4 weeks after implantation (1). Some patients with LVAD will require physical medicine and rehabilitation assessment and treatment to prepare them for outpatient CR due to profound deconditioning, frailty, and cachexia (wasting syndrome). Exercise prescription for patients with LVAD follows the same format as for other patients with heart failure. For patients with continuous-flow devices, exercise intensity should be prescribed on the basis of RPE of 11–14 (2).

Based on the results of the exercise test, an exercise prescription may be developed for the patient with the goal of maintaining or even improving cardiorespiratory fitness (to better tolerate surgery and early recuperation) while waiting for a donor organ. Ideally, the exercise program should be carried out under medical supervision, although many patients have performed home-based, independent exercise successfully. The exercise prescription follows the same guidelines used for other patients with chronic heart failure, as described in Chapter 12.

Heart Transplantation

Heart transplantation is the treatment of choice for eligible patients with advanced chronic heart failure resulting in markedly improved survival, functional status, and quality of life compared with alternative treatments (29). The Registry of the International Society for Heart and Lung Transplantation’s 2015 report (29) contained 112,521 heart transplantations performed worldwide between 1982 and 2013 with 1- and 5-year survival of 82% and 69%, respectively. Survival for 1 year was better for transplants performed between 2009 and 2013 (86%) than for earlier years. Survival is similar for both patients with and without circulatory support with an LVAD before transplantation. Causes of death include graft failure (primary graft dysfunction and acute rejection), infection, and multi-organ failure in the early years after surgery. Late mortality is due primarily to malignancy, cardiac allograft vasculopathy (CAV), and renal failure.

In 2013, there were 3,817 adult and 577 pediatric (≤18 yr) patients reported to the Registry worldwide (7,29). The age range of heart transplant recipients is from newborn to the eighth decade of life. For adults, the average age at transplant is approximately 54 years and 75% are men. Approximately 50% of children who receive a transplant are ≤5 years of age. The average age of the donors is approximately 35 years. Combined organ transplant (heart + liver, kidney or both, or heart-lung) accounts for 3% of transplants. Almost 70% of transplant candidates require pretransplant hospitalization, and mechanical circulatory support before transplant is common with 40% of patients with LVAD, 1% with a total artificial heart (TAH), and 1% with RVAD. Retransplantation accounts for 2.5% of cases.

The waiting time for an organ is dependent on blood type and the degree of medical urgency. Unfortunately, the number of potential candidates for heart transplantation greatly exceeds the available supply of donor organs. For example, for 2012, in the United States, 6,700 patients were eligible and listed for transplantation, but only 2,400 transplants were performed (49).

Approximately 90% of adult patients who require transplantation suffer from either coronary heart disease (ischemic left ventricular dysfunction, 45%) or idiopathic dilated cardiomyopathy (46%) (29). Additional diseases resulting in terminal heart failure include hypertension, valvular heart disease, myocarditis, alcohol abuse, chemotherapy, AIDS, complex congenital heart disease, infiltrative diseases of the myocardium (amyloidosis, hemochromatosis), and peripartum (19). For children, the most common indications for transplantation are complex congenital heart disease and cardiomyopathy (7).

Orthotopic transplantation, depicted in Figure 11.2, is the usual surgical technique with excision of the recipient’s diseased heart and anastomosis of the donor heart to the great vessels and atria of the recipient (42). Rarely, in the circumstances of excessive pulmonary vascular resistance with severe pulmonary hypertension, or a marked donor–recipient body weight mismatch, a heterotopic or “piggyback” transplant, shown in Figure 11.3, may be used. With this procedure, the recipient’s diseased heart is left intact and the donor heart is sewn in parallel to the existing heart. This procedure results in the unique electrocardiographic appearance of two separate QRS complexes on the electrocardiogram (ECG).

FIGURE 11.2. Orthotopic cardiac transplant technique. (From Squires RW. Exercise training after cardiac transplantation. Med Sci Sports Exerc. 1991;23:686–94.)

FIGURE 11.3. Heterotopic cardiac transplantation technique. (From Squires RW. Exercise training after cardiac transplantation. Med Sci Sports Exerc. 1991;23:686–94.)

Case Study 11-1 Quiz:

Description, Prevalence, and Etiology

1. What were the diagnosis and clinical findings that resulted in implantation of the LVAD?

2. What clinical factors and test factors (echocardiograms, cardiopulmonary exercise tests pre-LVAD vs. 85 days after LVAD) provide evidence that the LVAD improved the cardiovascular health of the patient?

Preparticipation Health Screening, Medical History, and Physical Examination

The goals of cardiac transplantation are improved survival, reduced symptoms, improved quality of life, and an increased exercise capacity. After recovery from surgery, most patients report an improved functional capacity (40). Many patients return to work, school, or their usual avocational activities, although exercise capacity generally remains below average as will be discussed later in the chapter. Employment for patients aged 25–60 years is approximately 50% (29). However, due to the immunosuppressant medications and other transplant-related factors, patients are prone to develop complications and comorbidities. Table 11.2 lists the prevalence of common medical problems observed in cardiac transplant recipients. In terms of medical screening for cardiac transplant patients, it is similar to methods used with patients who have undergone coronary bypass, coronary valve, or other cardiothoracic surgery.

Table 11.2

Cumulative Prevalence of Medical Problems in Survivors within Seven Years of Cardiac Transplantation

Condition	Prevalence
Hypertension	97%
Hyperlipidemia	89%
Cardiac allograft vasculopathy	43%
Renal dysfunction	36%
Diabetes mellitus	35%
Malignancy	24%

From Taylor DO, Edwards LB, Boucek MM, Trulock EP, Keck BM, Hertz MI. The Registry of the International Society for Heart and Lung Transplantation: twenty-first official adult heart transplant report — 2004. J Heart Lung Transplant. 2004;23:796–803.

Graft Dysfunction

The transplanted heart may fail soon after surgery due to primary graft dysfunction, pulmonary hypertension, or hyperacute rejection. Primary graft dysfunction is caused by ischemia and reperfusion injury related to the transplant procedure and results in the majority of early mortality (19). Contributing factors include brain death of the donor, ischemic time, and hypothermia of the donor heart. The incidence is variable but occurs in at least 5% of patients. The pathophysiology includes both increased pulmonary vascular resistance and systemic inflammation (22).

Rejection

Rejection of the transplanted heart is a major cause of hospitalization and death in the first year after surgery (51). There are four types of rejection: hyperacute, acute cellular, acute humoral (vascular), and chronic (CAV).

Hyperacute Rejection

Hyperacute rejection occurs shortly after surgery and is caused by preformed antibodies to the donor heart (51). This type of rejection results in acute inflammatory infiltration with vessel necrosis of the transplanted organ and patient death. Fortunately, with immunologic matching of donor and recipient, hyperacute rejection is rare.

Acute Cellular Rejection

Acute cellular rejection is most common during the first 6 months after transplantation, affecting approximately 50% of patients, and is due to T lymphocyte and macrophage infiltration of the myocardium (18). The diagnosis is made using routine, periodic transvenous endomyocardial biopsy of the right ventricle. If not treated promptly, myocardial injury and necrosis may occur, although mild acute cellular rejection may not require acute treatment (29). Based on tissue sample analysis, acute cellular rejection is graded from mild to severe. The treatment of acute cellular rejection involves additional immunosuppressants and may require hospitalization. Severe acute rejection, resulting in substantial myocyte necrosis and fibrosis, may produce left ventricular dysfunction and heart failure (42).

Acute Humoral Rejection

Acute humoral (vascular) rejection occurs within days to weeks of transplantation and is a relatively rare phenomenon (51). Initiated by antibodies, the process may impair coronary vasodilatory reserve resulting in ventricular dysfunction. Diagnosis is made by identifying immunoglobulins or complement in the vessels of the graft using biopsy material.

Chronic (Cardiac Allograft Vasculopathy) Rejection

CAV, also called chronic rejection or accelerated graft coronary artery disease, occurs months to years after transplantation (51). CAV is the major limiting factor in long-term survival after cardiac transplantation, affecting 43% of patients within 7 years of transplantation (see Table 11.2). The disease is an unusually accelerated form of coronary disease affecting epicardial and intramyocardial coronary arteries and veins (41). The pathophysiology is incompletely understood but is thought to be associated with repetitive immunological endothelial injury, ischemia-perfusion injury, viral infection, immunosuppressant medications, and traditional coronary risk factors such as dyslipidemia, insulin resistance, and hypertension. The lesions usually diffusely involve the entire vessel, although focal obstructive lesions are sometimes seen. This disease process occurs in pediatric and adult recipients with equal regularity. Annual coronary angiography or imaging stress testing may be performed to detect the disease. Because of the diffuse nature of the typical lesions, retransplantation is the most common treatment. In patients with discrete, focal lesions, revascularization, either catheter-based or coronary bypass graft surgery, may be effective.

Medications

Immunosuppressants

Immunosuppressant medications are given to prevent acute rejection of the donor heart (42). Maintenance drugs generally include combination therapy with a calcineurin inhibitor (sirolimus, tacrolimus, or cyclosporine), an antiproliferative agent ( mycophenolate mofetil or azathioprine), and a corticosteroid (prednisone) (28,51). These powerful drugs enable the patient to tolerate the donor heart but are associated with several common side effects as listed in Table 11.3. Prednisone, in the dose range used in transplantation, is particularly bothersome. It alters body fat distribution with resultant truncal obesity and a moonfaced appearance for many patients. Prednisone may also cause mood swings as well as skeletal muscle atrophy and weakness, osteoporosis, and dyslipidemia. During the first 1–2 years after transplantation, an attempt is usually made to taper and stop prednisone.

Table 11.3

Common Immunosuppressant Drugs and Associated Side Effects

Drug (Brand Name)	Potential Common Side Effects
Tacrolimus (Prograf)	Tremor, headache, diarrhea, hypertension, nausea, renal dysfunction
Sirolimus (Rapamune)	Skin irritation, tremor, light-headedness, weight gain, abdominal pain, diarrhea
Mycophenolate mofetil (CellCept)	Diarrhea, leukopenia, sepsis, vomiting, infection, edema
Prednisone	Muscle atrophy/weakness, hypertension, fluid retention, osteoporosis, aseptic necrosis of bone, “moon” face appearance, truncal obesity, increased insulin resistance, cataracts, glaucoma, mood swings, personality change, insomnia, peptic ulcer disease
Cyclosporine (Gengraf, Neoral, Sandimmune)	Renal dysfunction, tremor, hypertension, hirsutism, gum hyperplasia, muscle cramps, acne
Azathioprine (Imuran)	Nausea/vomiting, leukopenia, thrombocytopenia, anemia