Heart transplantation is the most effective treatment for end-stage HF refractory to medical therapy and pacing. To date, >120,000 heart transplants have been performed worldwide, and >3500 procedures are performed annually (http://www.ishlt.org). Despite this activity, the number of transplantations far from suffice to save the patients in need. The overwhelming reason for this is donor shortage. To this end, mechanical solutions in the form of LVADs are being increasingly used, either as a bridge to transplantation or as final therapy.
Indications for heart transplantations include terminal HF not responding to conventional therapy with an expected 1-year survival of <80%. This is typically estimated by selecting patients with advanced HF symptoms and a peak VO2 of <12mL/kg/min (<14 in patients intolerant of β-blockers).1 Contraindications (absolute and relative) include irreversible end-organ dysfunction, recent cancer, obesity (BMI >35kg/m2), certain chronic infections, fixed pulmonary hypertension, and importantly non-compliance or smoking, substance, or alcohol abuse. Age is not a contraindication, but most patients older than 70 years have comorbidity, leaving heart transplantation an unattractive therapeutic choice.
Median survival after heart transplantation in the registry from the International Society of Heart and Lung Transplantation (ISHLT), including data from the beginning of the registry, is 10.7 years, but >13 years when the analysis is restricted to transplants after 2002, clearly showing that survival is improving because of better patient selection, surgical techniques, and post-transplant medical management. Physical capacity, on average, is lower than that of age-matched controls, but heart transplantation is associated with an enormous improvement in peak VO2 and quality of life in the majority of patients. Most patients can return to work and lead an active life, including, for instance, travel and sports.
While prognosis after transplantation clearly has improved, multiple medical issues relating to acute or chronic graft rejection, as well as side effects from the necessary immunosuppressive therapy, remain. Leading causes of death late after transplantation include cancer, infection, and allograft vasculopathy (formerly termed chronic rejection). Chronic renal failure affects 20% 10 years after transplantation, and this is independently associated with inferior survival. Other important side effects of immunosuppressive drugs are discussed in Immunosuppression, p. [link], Induction therapy, p. [link], and Maintenance therapy, pp. [link]–[link].
Rejection of the donor heart results from the recipient’s immune system recognizing the transplanted organ as foreign and then mounting an immune response to it, either by antibody- or cellular-mediated mechanisms.
The main target of the recipient’s immune response towards the transplanted heart is the major histocompatibility complex (MHC) molecules. MHC molecules are expressed on the surface of a variety of cells and play a key role in the immune system, as they function to display allogeneic peptides to T-cells. In humans, the protein products of the MHC are termed the human leucocyte antigens (HLAs) and are classified into class I (A + B + C) and class II (DR + DQ + DP). HLA class I is present on most nucleated cells and can present alloantigens to a subtype of T-cells termed CD8+ T-cells, which may then trigger an immune response with cell lysis. HLA class II molecules are normally found on antigen-presenting cells (APCs) and display antigens to the CD4+ subtype of T-cells, which facilitate B-cell production of alloantibodies directed against the graft.
Recognition of an alloantigen from the donor by the host T-cells is the primary event which initiates the effector mechanisms of the adaptive immune response, leading to rejection. Donor antigen recognition by the T-cell depends on the binding of the T-cell receptor complex on the surface of the T-cell to an alloantigen/MHC complex on an APC. The APC can be either from the donor (direct pathway) or from the recipient (indirect pathway). In addition, T-cell activation is dependent on a co-stimulatory signal such as binding of the surface molecule CD28 on the T-cell to the surface molecule B7 on the APC. Once activated, T-cells undergo proliferation and differentiation by stimulation of a series of intracellular pathways and autocrine mechanisms, which are important targets of immunosuppressive therapies (see Fig. 3.2.1). Activation of the T-cell by binding to the allogen/MHC complex on the APC, together with the co-stimulatory signal, leads to increased cytoplasmic calcium (Ca2+) concentration, activation of calcineurin, and, in turn, dephosphorylation of the nuclear factor of activated T-cells (NFAT). NFAT then enters the nucleus and promotes transcription of interleukin-2 (IL-2), which leaves the nucleus of the T-cell and binds to the IL-2 receptor on the surface of the T-cell. Binding of IL-2 to the IL-2 receptor (CD27) activates the mammalian target of rapamycin (mTOR), which regulates transition through the cell cycle, leading to T-cell proliferation and differentiation. Based on the timing and underlying mechanisms, rejection is classified into hyperacute, acute, and chronic rejection.
Hyperacute rejection occurs immediately or within hours following transplantation with the reintroduction of blood into the graft. The hyperacute rejection results from preformed antibodies in the recipient to ABO antigens or HLA on the donor endothelium. Binding of preformed antibodies to donor antigens triggers complement and neutrophil activation, leading to extensive destruction of the donor endothelium, microvascular thrombosis, myocardial necrosis, and immediate graft failure. Risk for preformed HLA antibodies increases with pre-transplant blood product transfusions, previous solid organ transplantations, pregnancies, and treatment with durable mechanical ventricular assist systems. Hyperacute rejection is rare and can virtually be eliminated by ABO matching and pre-transplant screening for pre-existing HLA antibodies in the recipient.
Acute rejection is the commonest form of rejection in heart transplantation and is a potential cause of graft failure and death. The risk of rejection increases with younger recipient age, female gender, re-transplantation, and increased HLA mismatch between donor and recipient. The incidence of acute rejection requiring immediate intensified immunosuppressive treatment has decreased substantially over the last decades, along with improvements in immunosuppressive therapies.2 Currently, approximately 15% of adult patients will experience an acute rejection requiring treatment during the first year after transplantation, which is associated with increased long-term mortality. The risk of acute rejection is greatest in the first months after transplantation and then declines over the first year. Acute rejection may, however, develop at any time following heart transplantation, and lifelong immunosuppression is therefore required.
Acute rejection may be classified as either acute cellular rejection (ACR) or acute antibody-mediated rejection (AMR). ACR is the commonest form of acute rejection. It is mainly caused by T-cells directed against the myocardium of the donor heart, which, if severe, can result in myocyte necrosis and graft failure. ACR is graded based on histologically findings of endomyocardial biopsies, according to the ISHLT criteria, into no rejection (H0R), mild rejection (H1R) with interstitial and/or perivascular infiltrate with up to one focus of myocyte damage, moderate rejection (H2R) with two or more foci of infiltrate with associated myocyte damage, and severe rejection (H3R) with diffuse infiltrate with multifocal myocyte damage ± oedema ± haemorrhage ± vasculitis. The majority of mild rejections will resolve spontaneously on maintenance immunosuppressive therapy, whereas higher-grade rejections require supplemental immunosuppression such as IV methylprednisolone and, in severe cases, anti-thymocyte globulin (ATG).
Acute AMR is less well understood but seems to be predominantly caused by antibodies directed towards the vasculature of the donor heart, leading to complement activation and thereby damage of the vessels and consequently graft dysfunction. AMR can occur in isolation but often coincides with ACR. The grading of AMR, according to the ISHLT criteria, is based on both histopathologic and immunopathologic findings from endomyocardial biopsies. Although not part of the diagnostic criteria for AMR, the recipient may be screened post-transplantation for the formation of de novo donor-specific antibodies. The presence of strong and complement-binding donor-specific antigens may indicate the need for treatment, depending on graft function and the clinical situation.
Surveillance of acute rejection
Acute rejection may, if severe, lead to HF and arrhythmias with overt symptoms, but most often patients with mild to moderate rejections have no or only vague symptoms. Therefore, protocol-driven testing is standard practice, with endomyocardial biopsy as the gold standard for detection of rejection and guidance of immunosuppressive therapy. The timing of surveillance biopsies is centre-specific, but in general, biopsies are performed frequently (weekly) early after transplantation where the risk of rejection is greatest and less frequently over time as the risk of rejection declines, typically with the last planned biopsy 1–2 years after transplantation. Additional biopsies are performed when symptoms or cardiac imaging indicate otherwise unexplained graft dysfunction, after previous episodes of rejection, or following major reductions in the immunosuppressive medication such as weaning off corticosteroids or changing to a non-calcineurin inhibitor (CNI)-based immunosuppressive treatment.
Chronic rejection, now termed cardiac allograft vasculopathy (CAV), is a major cause of late graft failure and mortality after heart transplantation. CAV is a specific form of CAD, characterized by diffuse concentric intimal hyperplasia, which starts in distal small vessels and eventually involves the entire intramyocardial and proximal epicardial arteries. This contrasts with common atherosclerotic lesions which are usually located proximally and are focal and non-circumferential. The prevalence of CAV varies considerably, depending on how vasculopathy is defined and which method is used to detect it. When assessed by coronary angiography, the prevalence of CAV has been reported to be approximately 10% and 30% in survivors at 1 and 5 years after heart transplantation.3 As patients rarely experience angina due to cardiac denervation, surveillance is applied in most centres. Although angiography remains the most widely used method to assess CAV, this technique shows only the luminal diameters and therefore often misses the intimal thickening associated with early CAV. Using more sensitive techniques, such as intravascular ultrasound (IVUS) of the coronary arteries which provides a cross-sectional image of the wall structure, has demonstrated that CAV develops early after heart transplantation and is present in 50% of patients already 1 year after transplantation.3
Whereas multiple factors contribute to the development of CAV, immunologic mechanisms seem to play a predominant role, as both alloimmune and autoimmune responses are causal factors. In addition, many non-immune donor and recipient factors also affect the development of CAV, including hyperlipidaemia, hypertension, diabetes, cytomegalovirus (CMV) infection, and donor-derived CAD (ISHLT’s Thirty-First Official Adult Heart Transplant Report—2014). The net result of CAV is chronic graft failure, presenting either as systolic HF or as a restrictive cardiomyopathy with elevated filling pressures despite preserved ejection fraction. Another common presentation of CAV is sudden death.
Prevention of cardiac allograft vasculopathy
Studies have shown that the risk of CAV development depends on the immunosuppressive regimen used, with the lowest rates seen with proliferation signal inhibitors (PSIs). With respect to presumed non-immunologic factors, pravastatin and simvastatin given at the time of transplantation, irrespective of cholesterol levels, have been shown to reduce the risk of CAV in randomized trials. Hence, statins are used in all patients who tolerate them after transplantation. There are no studies documenting the effect on outcome for other cholesterol-lowering drugs. Target levels of blood cholesterol levels have never been established in this setting. Early data suggested that diltiazem was beneficial to prevent CAV, but studies performed in patients treated with statins could not confirm such an effect and diltiazem (which has a significant interaction with several immunosuppressants) are no longer routinely used after transplantation. It is unclear if ACEIs are efficient in preventing CAV. A recent randomized study did not show an effect on plaque burden but indicated that microvascular function might be improved with ramipril.4 Further studies to confirm this are needed. While there is no evidence that aspirin improves outcome after heart transplantation, it is customary to use it in patients diagnosed with CAV.
Treatment of cardiac allograft vasculopathy
Occasionally, proximal coronary lesions in patients with CAV may be treatable with PCI, and rarely, coronary artery bypass surgery is used. There are no randomized studies to inform about the utility of these strategies. The only definite treatment for severe CAV is cardiac re-transplantation. CAV is the commonest indication for re-transplantation, which accounts for 2–3% of all transplantations performed worldwide. Survival after re-transplantation is significantly lower than after a primary transplant.
Development of immunosuppressive therapies over the years has greatly improved survival in heart transplant patients by reducing the incidence of graft failure due to rejection. However, immunosuppression is associated with frequent and serious side effects, including renal failure, malignancies, diabetes, infections, hypertension, dyslipidaemia, neuropathy, and osteoporosis. Overall morbidity and mortality in transplanted patients are, to a large extent, driven by such side effects. The challenge of immunosuppressive therapy is therefore to balance between effects and side effects in the individual patient by continuous adjustment of the immunosuppression, according to the frequency and severity of rejection and the side effects caused by the therapy.
In general, immunosuppressive therapy in heart transplantation consists of a combination of immunosuppressive agents that differ by mechanism of action, thereby minimizing the side effects associated with each class of agent, while maximizing overall effectiveness. The different types of immunosuppression can be divided into induction therapy, which is given for a short period at the time of transplantation, and maintenance therapy, which is given lifelong after transplantation
Induction therapy mainly consists of polyclonal or monoclonal antibodies against T-lymphocytes. The aim of T-cell-specific antibody induction is to deplete or inhibit the proliferation of the circulating T-lymphocytes in the first days after transplantation, before the full effect of maintenance immunosuppressive treatment is reached, and thus to reduce the frequency and severity of early acute rejection. It has also been suggested that induction therapy may promote acceptance of the graft and allow for long-term reduction of maintenance immunosuppressive treatment. In addition, it may reduce the incidence of chronic allograft vasculopathy and ischaemia–reperfusion injury in the transplanted heart. However, T-cell-specific antibody induction causes profound immunosuppression and may increase the risk of infections, post-transplant lymphoproliferative disorder, and other malignancies. Although approximately 50% of centres use an initial antibody induction therapy, the advantage over an immunosuppressive protocol without induction is not clear and an overall survival benefit of induction therapy has not been demonstrated.
Polyclonal antibodies include rabbit and equine ATG. ATG is characterized by its polyclonal nature with a wide range of target molecules, constituting nearly 45 epitopes, ranging from antigens involved in immunity to adhesion and cell signalling molecules and cell surface antigens (Ruan Transplantation Proceedings, 2016). ATG given for induction therapy leads to rapid depletion of B- and T-cells. It is currently being used in approximately 20% of all adult heart transplantations (ISHLT registry slides 2016). Short-term side effects of these agents include thrombocytopenia, leucopenia, cytokine release, and serum sickness. To reduce the side effects induced by cytokine release, it is recommended to give IV corticosteroids and antihistamine before administration of ATG. In addition to its use in induction therapy, ATG is also used together with high-dose glucocorticoids to treat severe acute rejections.
Induction therapy by monoclonal antibodies
Currently, the most widely used monoclonal antibody for induction therapy in heart transplantation is the IL-2 receptor antagonist basiliximab, which is currently used in approximately 30% of adult heart transplants. This antibody does not deplete T-cells but reduces the risk of rejection by preventing clonal proliferation and differentiation of activated T-cells by blocking the IL-2 receptor. This class of compound was developed to increase the specificity of induction therapy, thereby avoiding the toxicity associated with the more diffuse effect of ATG. However, a more favourable outcome of IL-2 receptor antagonist, as compared to ATG, has not been demonstrated.
Several T-cell-depleting monoclonal antibodies have previously been available but have been withdrawn due to infrequent use. These included muromonab–CD3 specific for the CD3 receptor, and daclizumab and alemtuzumab targeting the CD52 surface protein.
Maintenance therapy is given lifelong after transplantation and generally consists of a combination of immunosuppressive agents that differ by mechanism. Such regimens may vary by patient and transplant centre but generally consist of a combination of three different agents, including a CNI (tacrolimus or ciclosporin), an antiproliferative agent [mycophenolate mofetil (MFA) or, less frequently, azathioprine (AZA)], and prednisolone. A more recent class of drugs, known as mTOR inhibitors or signal proliferation inhibitors, includes sirolimus and everolimus. These agents have been used in combination with an antiproliferative agent to allow for CNI dose reduction or withdrawal, as an alternative to an antiproliferative agent in combination with a CNI, or as a fourth agent in patients with ongoing rejection on conventional immunosuppressive therapy with a CNI, an antiproliferative agent, and prednisolone.
CNIs, including ciclosporin and tacrolimus, have remained the cornerstone of most maintenance immunosuppressive regiments in solid organ transplantation, including the heart. These compounds prevent T-cell proliferation and differentiation by inhibiting the enzyme calcineurin which, under normal circumstances, is responsible for activating the transcription of IL-2 leading to T-cell proliferation (see Fig. 3.2.1). The net result is blunting of T-lymphocyte activation and proliferation in response to alloantigens.
Ciclosporin was discovered in 1973 and was the first CNI approved for prevention and treatment of organ rejection by the FDA in 1983. It dramatically improved prognosis after organ transplantation by reducing graft failure due to rejection and substantially prolonged overall survival. To overcome the wide intra- and inter-individual differences in bioavailability of the original oil-based oral formulation of ciclosporin, a microemulsion formula of ciclosporin was introduced in the 1990s. Tacrolimus was discovered in the early 1980s and, from 1989, has been used for the prevention of liver transplant rejection. Since then, its use expanded rapidly into the transplantation of other organs.
Dosing of both oral ciclosporin and tacrolimus is typically titrated based on 12-h trough blood levels, with targets depending on the time since transplantation. In general, the levels are kept highest in the first month post-transplantation (e.g. 200–350ng/mL for ciclosporin and 10–15ng/mL for tacrolimus) and lowered in subsequent periods (e.g. 100–200ng/mL for ciclosporin and 5–10ng/mL for tacrolimus). However, target drug levels should be individualized to balance the risk of rejection with drug toxicities. Both ciclosporin and tacrolimus are available for IV administration where dosing should be reduced to about one-third of the oral dose for both drugs.
Both ciclosporin and tacrolimus have a wide range of side effects, including hypertension, infections, dyslipidaemia, neurotoxicity, diabetes, renal failure, and malignancy. When comparing ciclosporin with tacrolimus, tacrolimus seems to be associated with a lower risk of hypertension, hyperlipidaemia, gingival hyperplasia, and hirsutism. In addition, tacrolimus seems to be superior to microemulsion ciclosporin in heart transplant patients, with regard to survival and prevention of severe rejections.5 Due to this favourable profile of tacrolimus, it has now largely replaced the use of ciclosporin.2
Antimetabolites or antiproliferative agents interfere with the synthesis of nucleic acids and exert their immunosuppressive effects by inhibiting the cell cycle of both T- and B-lymphocytes. Antimetabolites include MMF, mycophenolate sodium, and AZA.
AZA was the earlier agent used in this class and served as the mainstay of immunosuppression, even prior to the routine use of ciclosporin. AZA is a prodrug that is first rapidly hydrolysed in the blood to its active form 6-mercaptopurine and subsequently converted to a purine analogue thio-inosine monophosphate. This antimetabolite is incorporated into deoxyribonucleic acid (DNA) and inhibits further nucleotide synthesis, thereby preventing mitosis and proliferation of rapidly dividing cells such as activated T- and B-lymphocytes. Major side effects include dose-dependent myelosuppression, particularly leucopenia. Other potentially serious side effects include hepatotoxicity and pancreatitis.
MMF is also a prodrug, which is rapidly hydrolysed to its active form mycophenolic acid, which is a reversible inhibitor of inosine monophosphate dehydrogenase, a critical enzyme for the de novo synthesis of guanine nucleotides. Lymphocytes lack a key enzyme in the guanine salvage pathway and are dependent upon the de novo pathway to produce purines necessary for ribonucleic acid (RNA) and DNA synthesis. Therefore, both T- and B-lymphocyte proliferation is selectively inhibited. By selectively targeting lymphocyte proliferation, MMF is less likely to produce neutropenia and anaemia than AZA, which affects the proliferation of all dividing cells. MMF is typically administered at a starting dose of 1000–1500mg bd, which is subsequently decreased in response to side effects, which mainly include dose-related leucopenia and GI toxicities such as nausea, gastritis, and diarrhoea. Drug monitoring is not routinely performed. Due to the superiority in survival and rejection with MMF versus AZA, MMF has now replaced AZA as the first-line antiproliferative drug. Also, MMF has been shown to reduce the risk of CAV, compared with AZA.6
Mycophenolate sodium is an enteric-coated, delayed-release salt of mycophenolic acid, developed to improve the upper GI tolerability of mycophenolate. It has shown similar effects to MMF, in terms of prevention of rejection, graft loss, and death, with better tolerability.7 Therefore, a switch from MMF to mycophenolate sodium may be attempted in patients with unacceptable GI side effects to MMF. A dose of 720mg of mycophenolate sodium corresponds to a dose of 1000mg of MMF.
Proliferation signal inhibitors
PSIs or mTOR inhibitors represent the most recent class of drugs used as maintenance therapy in solid organ transplantation. PSIs include sirolimus and everolimus, which have similar mechanisms of action. They inhibit mTOR, which is a protein kinase in the cytoplasm involved in the transduction of signals from the IL-2 receptor to the nucleus, causing cell cycle arrest at the G1 to S phase (see Fig. 3.2.1). The consequence of mTOR inhibition is a reduction of both T- and B-cell proliferation and a differentiation in response to IL-2. They are also known to inhibit the proliferation of endothelial cells and fibroblasts and may have a protective role against malignancies and CMV infections. While everolimus and sirolimus, when used as primary immunosuppressants together with CNIs, have proven efficacy in reducing rejection, compared with AZA, they have not yet been proven superior to MMF. The major advantages of mTOR inhibitors seem to be protection against chronic allograft vasculopathy, as assessed by IVUS of the coronary arteries, which has been documented in several randomized trials comparing PSIs to AZA, MMF, and CNIs.8,9 In addition, mTOR inhibitors may allow for reduced dosing, or even early withdrawal, of CNIs, leading to significant improvements in renal function by sparing the kidneys from the nephrotoxic effects of CNIs.
Side effects of PSIs include poor wound healing, stomatitis and oral ulcerations, dyslipidaemia, oedema, proteinuria, and non-infectious interstitial pneumonitis. To minimize side effects, regular monitoring of drug serum trough levels is recommended, targeting 5–10ng/mL for sirolimus and 3–8ng/mL for everolimus. Since PSIs potentiate the nephrotoxic effects of CNIs, it is important to reduce the dosing of CNIs if used in combination with a PSI.
Glucocorticoids are non-specific anti-inflammatory agents, with complex effects in the immune system that interrupt multiple steps, including antigen presentation, cytokine production, and proliferation of lymphocytes. Several dosing strategies exist for corticosteroid use, including high doses of IV methylprednisolone at the time of transplantation before tapering of oral prednisone to low maintenance doses begins. High-dose IV methylprednisolone is also used for treatment of episodes of moderate and severe acute rejections. Glucocorticoids have numerous side effects, including glucose intolerance, dyslipidaemia, increased appetite and obesity, osteoporosis, fluid retention, and a predisposition to opportunistic infections. Due to the many side effects associated with long-term use of glucocorticoids, a trial of steroid weaning is recommended in patients with a benign rejection history.10
Treatment of acute cellular rejection depends on several factors, including the severity, timing, and degree of side effects to the immunosuppressive medication. In general, if there is no rejection, one should consider if the immunosuppressive medication can be reduced to minimize side effects. A mild rejection most often does not require specific treatment, but it may be needed to increase maintenance therapy if drug levels are below targets. A moderate rejection (H2R) and severe rejection (H3R) are generally treated with high-dose glucocorticoid (e.g. 1000mg/day IV for 3 days). In severe rejection, cytolytic therapy with ATG should be considered if haemodynamic compromise is present. In addition, appropriate adjustments of maintenance immunosuppressive therapy should be made to decrease the risk of recurrent rejection. The optimal treatment of antibody-mediated acute rejection is less established but may, if associated with graft dysfunction, include plasmapheresis, IV immunoglobulin, and rituximab.
Drug interactions with immunosuppressive agents
CNIs and PSIs have a wide range of interactions with other medications, mainly through the P450 3A4 pathway. These interactions can create serious consequences in the absence of dose adjustments. Some of the drugs which increase the level of CNIs and PSIs include non-dihydropyridine CCBs, antifungals, and some antibiotics, including all macrolides and ciprofloxacin. Some of the common interactions which lead to reduced levels of CNIs include anti-seizure medications (phenytoin, carbamazepine, and phenobarbital) and rifampicin. These drugs can be used in combination with immunosuppressive therapy but require appropriate monitoring and dose adjustment. CNIs increase drug concentrations of statins, which should be started at low dosing, with slow uptitration. NSAIDs and aminoglycosides potentiate the nephrotoxic effects of CNIs and should be avoided. Allopurinol inhibits the metabolism of AZA, leading to a high risk of severe bone marrow suppression, and the combination should therefore be avoided.
Heart transplant patients receiving immunosuppressive medication are susceptible to infections. In the first month, patients are most susceptible to infection from donor-transmitted pathogens, as well as nosocomial bacterial and fungal infections. During months 1–6 post-transplant, opportunistic infections, such as Pneumocystis jiroveci, may develop, and the sustained level of maximal immune suppression increases the risk for infection from donor-transmitted, or reactivation of, viruses such as CMV and Epstein–Barr virus. Later, infections are dominated by community-acquired infections. Prophylactic treatment against infections may vary between centres but generally include antifungal prophylaxis such as oral nystatin treatment in the first weeks, CMV prophylaxis with oral ganciclovir or valganciclovir for the first 3 months, and anti-protozoal prophylaxis with trimethoprim/sulfamethoxazole usually at least 1 year post-transplant. General antibiotic prophylaxis for infectious endocarditis before dental procedures in cardiac transplant recipients is not recommended by the ESC Task Force. Inactivated vaccines are considered safe in heart transplant patients, and routine seasonal administration of inactivated influenza vaccine is recommended. Live virus vaccines are generally avoided following solid organ transplantation, given the potential for active infection.
Hypertension is common in heart transplant patients. Since antihypertensive treatment in heart transplant recipients has benefits similar to those in the general population, hypertension should be treated to achieve the same goals recommended for the general population. CCBs and ACEIs/ARBs are most commonly used. The non-dihydropyridine CCBs are generally well tolerated and do not require dose reduction of CNIs. In contrast, verapamil and diltiazem increase CNI levels and have negative inotropic effects and are nowadays rarely used for BP control in heart transplant recipients. β-blockers can also be used to treat hypertension but may be associated with decreased exercise capacity.
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