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6.9.2 Cardiovascular Disease
The underlying disease process and clinical course for CAV were described earlier
in this chapter.
• HMG CoA reductase inhibitors (statins): Statins should be prescribed for all
heart transplant recipients for primary prevention regardless of baseline lipids.
Both pravastatin and simvastatin have been shown to decrease the risk of CAV if
started soon after HTx [97]. In addition, pravastatin has the additional benet of
inhibiting natural killer cells to reduce the inammatory process [98]. Because of
drug interactions with calcineurin inhibitors, simvastatin is not recommended
rst line, although patients who have been taking it along with their immunosup-
pressant medications without problem may continue it. Pravastatin and rosuvas-
tatin (if a higher potency statin is indicated) are preferred statins in most solid
organ transplant recipients because of a lower risk of drug interactions as com-
pared to other statins.
• Aspirin: Aspirin 81mg daily is prescribed for all heart transplant recipients.
• Symptoms of heart disease should be assessed at each visit.
• CAV may present with very vague or atypical symptoms due to myocardial
denervation. Therefore it is essential to have a high level of suspicion for CAV
in heart transplant recipients who present with new-onset shortness of breath,
angina or malaise, and discuss with the transplant cardiology team.
• Heart failure symptoms or signs should also be discussed urgently with the
transplant team, as the patient may be having graft dysfunction.
• As noted above, the resting heart rate may be elevated due to lack of vagus
stimulation. If the heart rate is elevated over baseline, however, an ECG
should be obtained to look for both worsening sinus tachycardia as well as
other arrhythmias, both of which are associated with rejection.
• As discussed previously, CAV and rejection may be asymptomatic, explaining
the need for surveillance even without symptoms.
6.9.3 Chronic Kidney Disease
Due to CNI associated nephrotoxicity, CKD is common in patients after heart transplan-
tation and is seen in two-thirds of patients 10years after transplantation. After a decade,
10% of patients will either require dialysis or consideration for renal transplantation
[99]. The development of CKD is associated with non-modiable risk factors, such as
age, gender, and time since transplant as well as modiable risk factors, including dia-
betes and hypertension [100, 101]. While the transplant cardiologist will tailor the
immunosuppression regimen if needed because of the onset or worsening of CKD, the
primary care provider can collaborate in the management of hypertension, diabetes, and
other comorbidities that affect renal function. All heart transplant recipients should
avoid any use of non-steroidal anti-inammatory medications.
6 Primary Care oftheAdult Heart Transplant Recipient
158
6.9.4 Cancer
Malignancy is the fourth most common cause of death after transplantation and occurs
in the setting of chronic immunosuppression [102]. Skin malignancies are the most
common cancer, followed by lymphoma, and any history of pre-transplant malig-
nancy increases the risk of malignancy after transplant [103]. Male gender and recipi-
ent age>50years may also be associated with an increased risk of cancer [104]. Heart
transplant recipients should receive an annual dermatology examination. The risk of
malignancy may potentially be mediated by varying the immunosuppression regimen.
Emerging data show that conversion to sirolimus is associated with decreased risk for
de novo malignancies and post-transplant lymphoproliferative disorders, with
improved long-term survival; however, routine use is limited by medication intoler-
ance due to side effects. Sirolimus is not used as rst-line therapy as it impairs wound
healing immediately post-transplant, and there has been mixed data suggesting a pos-
sible increased risk for rejection compared to CNI’s [56]. (See Chap. 10).
6.9.5 Hypertension
Due to abnormal cardiorenal neuroendocrine reexes, heart transplant recipients
have a decreased natriuretic and diuretic response and therefore have particularly
salt-sensitive hypertension [105]. In addition, blood pressure is often elevated due
to the impact of calcineurin inhibitors and glucocorticoids. Cyclosporine and tacro-
limus are associated with an especially high incidence of hypertension after trans-
plantation [106]. Although glucocorticoids are weaned over time, long-term
calcineurin inhibitor therapy is expected. Treatment of hypertension is especially
important because both calcineurin inhibitors and systemic hypertension can con-
tribute to the development of chronic kidney disease [107]. The author group typi-
cally favors treating hypertension with respect to comorbidities: e.g., ACE-inhibitor
(ACEi) or angiotensin receptor blocker (ARB) in patients with diabetes or CKD,
thiazide diuretics for patients with a tendency to retain volume. Amlodipine is con-
sidered for patients who are intolerant or do not benet from those therapies. If
additional therapy is needed, we typically initiate hydralazine next. There is data
suggesting that ACEi/ARB or dihydropyridine calcium channel blockers may pro-
tect against CNI-induced vasoconstriction so these medications may be considered
preferentially. Beta-blockers are uncommonly used after heart transplantation, but
when used for hypertension, a nonselective agent such as carvedilol is preferred.
Caution must be exercised with patients early-post-heart transplant as many patients
are dependent on their higher heart rate and can be very sensitive to beta-blockers
from upregulation of their beta-receptors due to relying on circulating catechol-
amines from donor heart denervation, particularly early after heart transplant. It is
important to avoid agents that may be implicated in drug-drug interactions such as
diltiazem which is a CYP3A4 inhibitor. (See Chaps. 3 and 11).
V. P. Nguyen et al.
159
6.9.6 Diabetes
Due to chronic glucocorticoid therapy, heart transplant recipients are at risk for
hyperglycemia and diabetes. Although diabetes may resolve over time as patients
are weaned off their steroids, calcineurin inhibitors may cause ongoing post-
transplant diabetes (PTDM). The risk of developing PTDM parallels the degree of
pre-transplant glucose intolerance and confers an increased long-term mortality risk
in heart transplant recipients [108, 109]. However, with improved PTDM manage-
ment, this mortality risk can be mitigated [110]. Primary care providers can assist in
the management of post-transplant diabetes. Treatment options for PTDM mirrors
that of non-transplant cardiac patients and includes insulin, sulfonylureas, glinides,
thiazolidinediones, SGLT2i and GLP1RA if graft function is normal, and metfor-
min if tolerated by the renal function. (See Chap. 11).
6.9.7 Infectious Endocarditis Prophylaxis
Compared to the general population, heart transplant recipients have a higher inci-
dence of infective endocarditis (IE) [111]. Although the risk of dental procedures in
causing IE in heart transplant recipients is not well known, IE in the transplanted
heart can have devastating effects and is associated with increased mortality. Based
on the 2007 AHA guidelines, heart transplant recipients should receive infective
endocarditis prophylaxis for all dental procedures that involve manipulation of den-
tal tissues [112]. A suggested regimen is amoxicillin 2000mg given orally 1hour
prior to dental procedures.
6.9.8 Pregnancy
Pregnancy is generally not encouraged after heart transplantation but is not abso-
lutely contraindicated. Nevertheless, if a patient desires pregnancy, she should dis-
cuss with her heart transplant specialist about her individualized risks, and in most
cases, perinatal care should be coordinated by a multidisciplinary team of providers,
including a transplant cardiologist, maternal fetal medicine specialist, neonatologist,
psychologist and social worker [113]. Throughout pregnancy and in the immediate
post-partum period, the patient should be closely monitored for graft dysfunction
and rejection when pregnancy occurs. We recommend close monitoring of the left
ventricular function. As most immunosuppressive therapy regimens have some
degree of teratogenic potential, certain changes can be made to increase the chance
of successful pregnancy [114]. Given the rare occurrence of pregnancy in this popu-
lation, no ofcial guidelines exist on this topic. Mycophenolate should be stopped
and the patient can often be maintained on tacrolimus monotherapy. If a second
agent is needed, azathioprine can be considered. (See Chap. 13)
6 Primary Care oftheAdult Heart Transplant Recipient
160
6.9.9 Activity andExercise
As with other patients who undergo open-heart surgery, there are strict sternot-
omy precautions following discharge from the hospital. During this early period,
patients are most likely primarily cared for by the transplant team. Following
heart transplantation, patients are typically referred to cardiac rehabilitation on
discharge. Although rehabilitation has not been shown to improve quality of life
at 1 year, exercise-based cardiac rehabilitation does improve exercise capacity
in the recovery period [115]. Due to the issues of denervation and chronotropic
incompetence, patients should warm up prior to physical activity to stimulate
catecholamine circulation and increase their heart rate. Abrupt transition from
stop-to-start may not be well tolerated due to the lack of normal sympathetic
innervation. When the heart transplant recipient returns to primary care, the
primary care provider should review the transplant team’s recommendations for
activity level for a given patient.
6.9.10 Diet
Most end-stage heart disease patients experience cardiac cachexia prior to heart
transplantation and as patients recover from their surgery, this condition typically
reverses with improved functional status [116]. Dedicated dietary counseling may
improve metabolic derangements and should be considered [117]. For prevention of
infection, heart transplant recipients should not consume raw meats or raw sh. Any
meat from a deli should be microwaved prior to consumption. Early after transplant,
patients must follow a carbohydrate-managed diet while they are on high-dose glu-
cocorticoids, and although the glucocorticoid dose is typically weaned over time,
risk of diabetes persists and patients should still have a heart healthy diet without
excessive carbohydrates. Many patients require additional dietary modications if
they develop chronic kidney disease. Salt should be limited in the presence of uid
retention and hypertension.
6.10 Case Studies
1. A 40-year-old man underwent heart transplant 6months ago and now presents to
the primary care setting with diarrhea. He had end-stage heart failure due to familial
cardiomyopathy, and was bridged with LVAD prior to transplantation. His initial
course was complicated by early graft dysfunction, but this improved several days
after surgery. He was discharged to home and has had regular follow-up with the
transplant team. His routine surveillance for rejection has been negative. He is CMV
Donor+/Recipient-. He now has frequent episodes of watery diarrhea, up to eight
episodes per day, without abdominal pain, melena, hematochezia, nausea, or
V. P. Nguyen et al.
161
emesis. His weight has been stable. He has no chest pain, dyspnea, or fever. On
examination he is afebrile with a normal blood pressure and a heart rate of 90 which
is baseline for him since transplantation. His cardiac, pulmonary, and abdominal
exams are normal.
6.10.1 How Should this Patient BeManaged?
In a heart transplant recipient who presents with diarrhea, it is important to exclude
infection. If the patient is stable, a serum cytomegalovirus (CMV) DNA quantica-
tion test should be sent as well as a stool enteric pathogen panel. Stool pathogen
panels vary by laboratory—if acute diarrhea, a standard bacterial panel should be
tested; if recent antibiotics or hospitalization, then clostridium difcile PCR should
be tested. Testing for parasitic infections should strongly be considered for chronic
diarrhea, especially in endemic regions or if there are any exposures to susceptible
food or water sources. Diagnosis of CMV colitis is conrmed on pathology—there-
fore consultation with a gastroenterologist may be needed to perform an endoscopy.
The transplant team should be alerted to this workup, and if testing is negative, they
may consider reassessing his medications, as mycophenolate mofetil and magne-
sium oxide are common causes of diarrhea in transplant recipients. Unstable patients
should be transferred to an acute care setting such as the emergency department in
case volume resuscitation or a more rapid workup and treatment is needed.
In his case, the infectious studies are negative. He is switched from MMF to
MPA and his magnesium supplementation is changed to a slow-release formulation.
In addition, he is prescribed loperamide as needed and supplemental ber. On a
follow-up phone call several days later, the patient notes his stools are much
improved (See also Chap. 9).
6.10.2 Case Study
2. A 69-year-old man with history of ischemic cardiomyopathy undergoes heart
transplantation. He received rATG induction and was started on a standard regimen
of tacrolimus, MMF, and prednisone. His initial course was notable for leukopenia
thought to be secondary to the rATG induction. He required temporary holding and
then reduction of his mycophenolate mofetil; additionally, valganciclovir was
stopped, sulfamethoxazole/trimethoprim was switched to dapsone, and his counts
recovered. 8months later he presents to primary care and asks to review his most
recent labs. He had been seen in urgent care for a respiratory infection and had a
CBC drawn. His respiratory symptoms have since resolved.
The primary care provider reviews his transplant course to date; notable for no
rejection episodes and good graft function. His laboratory studies show a white
blood cell count of 1.3 thousand/microliter and an absolute neutrophil count of 700/
microliter.
6 Primary Care oftheAdult Heart Transplant Recipient
162
6.10.3 How Should this Patient BeManaged?
There are many potential causes of cytopenias in the heart transplant recipient.
Leukopenias may be caused by several factors. rATG induction is a common cause
of leukopenia in patients early post-HTx. The primary care provider is likely not
involved closely in care at that point in time, but if there are episodes of rejection
requiring additional rATG, then PCPs should be aware that recurrent leukopenia
can occur.
In addition, other routine post-transplant medications that can result in neutrope-
nia include MMF, prophylactic valganciclovir, and sulfamethoxazole/trimethoprim.
The medication list should be reviewed for the presence of any non-transplant medi-
cations that may cause cytopenias themselves or have drug interactions with the
transplant medications. In a stable patient, the CBC should be repeated. If persistent
or severe leukopenia is seen, then the PCP should discuss this urgently with the
transplant team. The PCP should not adjust any transplant medications without
consultation.
In this case, the patient’s MMF was held, but he continued to have recurrent
leukopenia when rechallenged. Based on the TICTAC study and his advanced age,
his transplant team transitioned him to tacrolimus monotherapy. He does well on
monotherapy without any clinical rejection. If there were concern for rejection on
monotherapy going forward, an alternative regimen would be low-dose tacrolimus
in combination with sirolimus with close monitoring of renal function, diabetes and
wound healing. Conversely, azathioprine would not be a good option as it is also
myelosuppressive.
6.10.4 Case Study
3. A 40-year-old woman with a history of non-ischemic cardiomyopathy underwent
heart transplantation. Her post-transplant course had been unremarkable. She takes
her immunosuppression consistently and has not missed any doses. 10years later,
she presents with slow-onset, progressive dyspnea on exertion and fatigue. She
denies any chest pain. Her examination shows normal lung and heart exam, no
peripheral edema or elevated jugular venous pressure.
6.10.5 How Should this Patient BeManaged?
An ECG can be obtained in clinic. A routine chest X-ray and laboratory studies to
look for anemia should be obtained. In many cases, the heart transplant recipient
will not have classic symptoms of angina even if they have coronary vasculopathy
as the heart is denervated. Over time, the heart can become re-innervated so angina
V. P. Nguyen et al.
163
can occur in some instances, but the absence of angina should not preclude evalua-
tion for coronary vasculopathy. If the patient is clinically unstable, frequently with
heart failure symptoms, then more urgent evaluation an emergency setting should
be facilitated. In this case, as she is clinically stable, an expedited outpatient workup
may be performed. The transplant cardiologist should be contacted.
An urgent echocardiogram is obtained and shows new hypokinesis of the lateral
wall. She undergoes urgent cardiac catheterization and is found to have left circum-
ex disease consistent with CAV. Unfortunately, despite percutaneous coronary
intervention, she develops progressive diffuse coronary vasculopathy and ultimately
undergoes retransplantation.
6.10.6 Case Study
4. A 28-year-old woman with a history of familial cardiomyopathy underwent heart
transplantation. Her immediate post-transplant course was unremarkable and she
was discharged 2weeks after heart transplant. She comes in to see you 6months
after heart transplant for a general PCP visit. She has not missed any of her immu-
nosuppression medications but recently her clotrimazole was stopped. Over the last
few days, she has noted progressive dyspnea on exertion and fatigue, 10 pound
weight gain, swelling in her lower extremities and abdominal bloating. Her exami-
nation shows elevated jugular venous pressure, tachycardia, normal rhythm, pres-
ence of a S3, bibasilar rales, mildly distended abdomen, and bilateral pitting edema.
6.10.7 How Should this Patient BeManaged?
This patient appears to be in acute heart failure with her recent symptoms, rapid
weight gain and based on physical examination. After heart transplant, this should
be viewed as a medical emergency and the patient should be sent to the emergency
room for admission and the transplant cardiologist immediately notied. The trig-
ger for her episode of acute rejection was likely due to stopping her clotrimazole,
which is used early after heart transplant to prevent thrush when on high-dose cor-
ticosteroids but is tapered to off once the steroid dosing is lower. Due to drug–drug
interactions between -azoles and calcineurin inhibitors such as tacrolimus (where
the -azoles will “boost” the tacrolimus levels), when the clotrimazole is stopped, the
tacrolimus dose needs to be increased. In her case, the tacrolimus dosing might not
have been increased sufciently resulting in subtherapeutic immunosuppression
and acute rejection. In a heart transplant recipient, any new medication should be
checked for drug-drug interactions before initiation as many medications can inter-
act with tacrolimus and alter the drug levels.
In the emergency room, she underwent an urgent echocardiogram showing LVEF
of 35% with increased wall thickness. Her B-type natriuretic peptide and serum
6 Primary Care oftheAdult Heart Transplant Recipient
164
troponin-I were elevated. Given high clinical suspicion for acute rejection, she was
started on high-dose IV corticosteroids with solumedrol 500mg IV.She then under-
went right heart catheterization and endomyocardial biopsy showing elevated left
and right-sided lling pressures, low cardiac output, consistent with acute rejection.
Her endomyocardial biopsy showed ISHLT 2004 grade 2 rejection. She was treated
with methylprednisolone 500mg IV daily×3days, rabbit ATG ×3 doses, and tran-
sitioned to an oral prednisone taper in addition to her current regimen of tacrolimus
and mycophenolate. Fortunately, she recovered her cardiac function.
6.10.8 Case Study
5. A 50-year-old man suffered a large anterior myocardial infarction with persistent
reduction in his LVEF, presenting with worsening heart failure and undergoes heart
transplantation (CMV Donor+/Recipient+, EBV Donor+/Recipient-). His post-
transplant course was mostly unremarkable and he returned to his baseline activity
level including returning to work. He is seeing you for a routine visit 5years after
heart transplant but notes generalized fatigue, low grade fevers, unintentional weight
loss, and fullness under his axilla and jaw over the last 2months.
6.10.9 How Should this Patient BeManaged?
His clinical presentation is concerning for post-transplant lymphoproliferative dis-
order (PTLD). PTLD often presents with nonspecic symptoms and can be mis-
taken for a viral illness. In this case, he is at particularly increased risk for PTLD
due to the EBV mismatch at the time of heart transplant. Of specic concern is the
constellation of symptoms in combination with his lymphadenopathy.
He undergoes CT scan of the chest, abdomen and pelvis showing diffuse lymph-
adenopathy. He is referred to hematology/oncology, where additional work-up
including biopsy of the lymph nodes and bone marrow biopsy conrms the diagno-
sis of PTLD.His heart transplant cardiologist reduces the immunosuppression regi-
men substantially to increase immunosurveillance and the immune response to his
cancer. He is treated with a rituximab-based regimen, as well as antivirals for the
EBV and responds, achieving complete remission.
6.10.10 Case Study
6. A 58-year-old man with a history of diabetes mellitus type II, hypertension,
chronic kidney disease, and ischemic cardiomyopathy undergoes heart transplant.
During the process of evaluation for heart transplant, he was noted to have CKD and
V. P. Nguyen et al.
165
mild proteinuria, but not sufcient to warrant combined heart and kidney transplan-
tation. After heart transplant, attempts to transition him to sirolimus were not toler-
ated due to GI side effects and he has remained on tacrolimus long-term. Attempts
were made to decrease his tacrolimus trough target levels, but he developed low
grade rejection requiring increasing his trough target levels again. He is seeing you
for routine follow-up 3years after heart transplant but tells you he has been very
fatigued, sleepy, and nauseated recently. At baseline, his creatinine has been in the
2.0mg/dL range. His labs today show rising BUN to 110mg/dL and rising creati-
nine to 4.3mg/dL.
6.10.11 How Should this Patient BeManaged?
This patient should be admitted for further evaluation and exclusion of acute
causes for his kidney dysfunction, which would encompass the standard work-
up for acute kidney injury AKI), but also consideration for medication induced
AKI (such as thrombotic microangiopathy from tacrolimus or hemolytic uremia
syndrome). If acute causes are excluded, his progressive kidney dysfunction
may be attributed to long-term toxicity from calcineurin inhibitor exposure
from the tacrolimus. In many instances, in individuals with CKD, attempts will
be made to transition to a calcineurin inhibitor free regimen with MTOR inhibi-
tors or minimizing the calcineurin inhibitor trough target levels for renal spar-
ing. However, in this case he was intolerant of MTOR inhibitors and remains on
tacrolimus long-term. His fatigue and nausea are likely due to his uremia.
Once an individual has severe CKD from calcineurin inhibitor toxicity, kidney
transplant should be considered in select individuals as calcineurin inhibitor induced
CKD tends to be progressive particularly in cases where the calcineurin inhibitor
cannot be stopped or minimized. In this case, he did not tolerate MTOR inhibitors
and attempts to lower his tacrolimus trough levels resulted in rejection so his tacro-
limus dosing could not be reduced.
6.11 Conclusion
Survival following heart transplantation continues to improve over time [118]. The
median survival is expected to be 15years in the current era [119]. Following heart
transplantation, most patients experience a signicant improvement in their quality
of life. However, close monitoring for complications and preventive health remains
essential to maintain this quality of life. Primary care providers can contribute
greatly in the assessment and management of the health of heart transplants recipi-
ents as they partner with the transplant team.
6 Primary Care oftheAdult Heart Transplant Recipient
166
Acknowledgments
We would like to thank Beatrice S.Wong, PharmD for reviewing the accu-
racy of information in this chapter. We would also like to thank the University of Washington Heart
Transplant Team, including the physicians, coordinators, and allied staff for their collaborative
care for our patients.
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