Cardiac transplantation and mechanical circulatory support.
- Heart transplantation
- Mechanical circulatory support
- Further reading
Cardiac transplantation is the treatment of choice for selected patients with advanced heart failure: median survival exceeds 10 years and recipients enjoy an excellent quality of life, but availability is severely limited by shortage of donor organs. The need for life-long immunosuppression is associated with side effects, including an increased incidence of malignancy. Newer immunosuppressive agents offer promise in reducing nephrotoxicity of conventional regimens and in delaying the onset of (currently inevitable) cardiac allograft vasculopathy.
Mechanical circulatory support
Ventricular assist devices (VADs) are mechanical blood pumps that work in parallel or series with the native ventricle: there are two main types—pulsatile, also referred to as volume displacement, and rotary. Significant complications arise from bleeding, thromboembolism, and infection.
Short-term use—several devices are available for use in patients who need support for days to periods of up to 4 to 6 weeks: these are invaluable in postcardiotomy cardiogenic shock and in patients who present in extremis with multiorgan failure.
Longer-term use—implantation of a device in patients with chronic heart failure must be viewed either as a bridge to heart transplantation or as permanent support. The REMATCH study (Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure) randomized patients with endstage heart failure to best medical therapy or the implantation of the HeartMate I assist device: survival was improved in the device group (52% vs 25% at 1 year; 23% vs 8% at 2 years).
In 1964 James Hardy transplanted a chimpanzee heart into a 68-year old man with ischaemic heart failure, but the patient did not survive surgery. The first human-to-human heart transplant was performed in Cape Town on 3 December 1967 by Christiaan Barnard; the patient died 18 days afterwards of infective complications. By the end of 1968, 102 patients had received heart transplants in 50 hospitals in 17 countries: mean survival was only 29 days and there was widespread disenchantment with the procedure. Few institutions continued clinical cardiac transplantation in the 1970s, the team at Stanford University under the leadership of Norman Shumway being pre-eminent amongst them. By the late 1970s 1-year survival at Stanford had increased to 65%, establishing the place of heart transplantation. The introduction of new immunosuppressive drugs in the 1980s led to further improvement in outcome and an explosion of activity around the world. Over the last decade there has been a decline in the number of heart transplants performed owing to a lack of donor organs.
Heart transplantation is the treatment of choice for selected patients with endstage heart failure. However, the number of available donor organs restricts this treatment to a small fraction of potential recipients. Careful selection of patients is therefore crucial to use scarce donor organs to best effect. Patients with NYHA Class IIIB and Class IV heart failure are best discussed with the local heart failure/transplant centre to optimize medical management and to consider high-risk non-transplant surgery where appropriate. Patients with chronic heart failure should be referred before they develop significant renal and hepatic dysfunction and irreversible pulmonary hypertension. Bullet list 1 summarizes criteria used to select patients for transplantation, with the use of cardiopulmonary exercise testing to objectively quantify functional capacity and to estimate prognosis is an important part of the assessment process. Bullet list 2 outlines the important contraindications.
Bullet list 1 Indications for heart transplantation
- ◆ Ongoing symptoms of heart failure at rest or minimal exertion despite optimal medical therapy. Functional capacity measured by peak oxygen uptake on exercise <14 ml/kg per min (or 50% predicted). For patients receiving β-blockers a value of 12 ml/kg per min has been recommended
- ◆ History of recurrent admissions to hospital with worsening heart failure
- ◆ Refractory ischaemia not amenable to revascularization associated with severe impairment of left ventricular function
- ◆ Recurrent symptomatic ventricular arrhythmia associated with severe impairment of ventricular function
Bullet list 2 Contraindications to heart transplantation
- ◆ Active infection (including chronic viral infections, e.g. HIV, hepatitis B)
- ◆ Symptomatic peripheral or cerebrovascular disease
- ◆ Diabetes mellitus with end-organ damage (nephropathy, neuropathy, proliferative retinopathy)
- ◆ Coexistent or recent neoplasm
- ◆ Severe lung disease (FEV1 and FVC <50% predicted)
- ◆ Renal dysfunction with creatinine clearance less than 40 ml/min
- ◆ Recent pulmonary thromboembolism
- ◆ Pulmonary hypertension (pulmonary artery systolic pressure >60 mm Hg, transpulmonary gradient ≥15 mmHg and/or pulmonary vascular resistance >5 Wood units)
- ◆ Psychosocial factors including history of noncompliance with medication, inadequate support, drug or alcohol abuse
- ◆ Obesity (body mass index >30 or weight >140% of ideal body weight
- ◆ Age (usually >65 years)
Matching of donor and recipient
Donor and recipient blood groups need to be compatible. Appropriate size matching is also generally thought to be necessary to minimize donor organ failure. HLA matching is not routinely carried out, but there is some evidence that HLA-DR matching results in fewer episodes of acute rejection.
Most patients spend 2 to 3 weeks in hospital after a heart transplant and are fit to return to work after 4 to 6 months. In the first year they need to return to the transplant centre frequently to monitor immunosuppression, and to have surveillance endomyocardial biopsies to detect acute rejection, although recent studies suggest that – at least for low-risk patients – a non-invasive monitoring strategy involving gene-expression profiling of peripheral blood mononuclear cells may be a safe alternative to endomyocardial biopsy..
Immunosuppression is commenced at surgery and continued for life. The intensity of immunosuppression is greatest early post-transplant, with a gradual decrease in the dosage of drugs over the first year. Bullet list 3 lists the agents commonly used for maintenance immunosuppression: some patients receive additional antibody therapy for the first few days after the transplant. At least 50% of patients can be safely weaned off prednisolone in the first 2 years after surgery. Episodes of acute rejection (usually confirmed by endomyocardial biopsy) are treated with intravenous methylprednisolone and are almost always reversible.
Bullet list 3 Immunosuppressive drugs
- ◆ Calcineurin inhibitor: ciclosporin or tacrolimus
- ◆ Antimetabolites: mycophenolate mofetil or azathioprine
- ◆ Corticosteroid: usually prednisolone
- ◆ Target of rapamycin (TOR) inhibitor: sirolimus or everolimus
Median survival now exceeds 10 years in most large centres. Annual mortality after the first year is approximately 3.5% per year. Most patients enjoy an excellent quality of life after a heart transplant, with minimal or no functional limitation. Successful pregnancy is possible after heart transplantation: management requires close collaboration between transplant and obstetric teams. Maternal morbidity is higher than in the general population and there is a higher incidence of small for date babies. Teratogenicity does not seem to be a significant problem with the immunosuppressive regimens used in the 1980s and most of the 1990s (steroids, azathioprine, calcineurin inhibitors), but the same cannot be said of many of the newer agents.
General complications related to immunosuppression include an increase in opportunistic infection and malignancy, in particular squamous cell carcinoma of the skin and non-Hodgkin’s B-cell lymphoma (which affects 2% of heart transplant recipients). Calcineurin inhibitors can cause headaches, tremor, hypertension, nephropathy, and peripheral neuropathy, and exacerbate myalgia/myositis associated with statin use. Corticosteroids are associated with osteoporosis and diabetes. Ciclosporin can cause hirsutism and gum hypertrophy. Issues particular to cardiac transplantation are described below.
Abnormalities in lipid levels have been reported in up to 80% of patients on standard immunosuppressive drug regimes. Pretransplant abnormalities are common in patients transplanted for heart failure secondary to coronary artery disease. Use of statins early post-transplant has been shown to delay the onset of cardiac allograft vasculopathy and reduce mortality after heart transplantation and is now standard practice in most units.
The most serious specific side effect of calcineurin inhibitors is renal dysfunction. Data from the International Society for Heart and Lung Transplantation indicate that about 20% of patients have some degree of renal dysfunction at 1 year after transplantation. Afferent renal arterial vasoconstriction is believed to be the cause of early renal dysfunction and is reversible. Late renal dysfunction is related to tubular damage and tends to be progressive, even when the offending drug is discontinued. At least 5 to 6% of heart transplant patients progress to require renal replacement therapy in the first 10 years post-transplant, and their prognosis on dialysis is poor. The recent introduction of calcineurin inhibitor-free regimes will, it is hoped, decrease the incidence of renal failure. Selected patients with good cardiac function can be considered for renal transplantation.
Cardiac allograft vasculopathy
This term is used to describe concentric narrowing of the coronary arteries (and sometimes veins) of the transplanted heart. It is believed to be an immune mediated disease and is also referred to as ‘chronic rejection’, although nonimmune mechanisms probably contribute to pathogenesis. It is the commonest cause of late death after heart transplantation but occasionally presents as a fulminant process that causes death within the first year. Conventional risk factors like smoking and hyperlipidaemia are associated with earlier disease, but cardiac allograft vasculopathy occurs in children and in the absence of other risk factors.
The basic pathological lesion is a diffuse and progressive thickening of the intima that occurs in epicardial and intramyocardial arteries. The disease tends to affect the arterial tree diffusely, although there is heterogeneous involvement of different parts of the arteries. The degree of intimal thickening that occurs in the first year (measured by intravascular ultrasonography) is a predictor of the development of angiographic disease and death or retransplantation for cardiac allograft vasculopathy, risk factors for which are shown in Bullet list 4
Bullet list 4 Risk factors for cardiac allograft vasculopathy
- ◆ Number of episodes of acute rejection
- ◆ HLA DR mismatch between donor and recipient
- ◆ Anti-HLA antibodies in the recipient (associated with the deposition of antibody and complement in the vasculature of the allograft)
- ◆ Donor age
- ◆ Recipient age and gender
- ◆ Coronary artery disease as the cause for transplantation in the recipient
- ◆ Cytomegalovirus infection
- ◆ Smoking
- ◆ Obesity
- ◆ Hyperlipidaemia
Most patients with cardiac allograft vasculopathy present with signs and symptoms of heart failure, although angina can be experienced despite denervation. The disease is commonly first seen during surveillance coronary angiography. Revascularization is rarely feasible because the disease is diffuse, but occasionally patients have focal proximal lesions that are amenable to angioplasty.
Intravascular ultrasonography (IVUS) is the most sensitive technique for diagnosis of early disease and most clinical trials of new immunosuppressive drugs include IVUS-derived parameters as an endpoint. The only definitive treatment for cardiac allograft vasculopathy is retransplantation, which—given the shortage of donor organs—is an option for only a few patients. Target of rapamycin (TOR) inhibitors may delay the onset and slow the progression of cardiac allograft vasculopathy.
Mechanical circulatory support
The concept of arterial counterpulsation to unload the heart in systole was introduced in the early 1960s. This led to the development of the intra-aortic balloon pump, which was first applied clinically by Kantrowitz in 1967. In 1966 DeBakey reported the first successful clinical application of a true ventricular assist device in a 37-year old woman who could not be weaned from cardiopulmonary bypass following aortic and mitral valve replacement. In 1969 Cooley supported a patient with a total artificial heart for 64 hours until a donor heart was available. In 1984 Stanford University reported the first successful heart transplant following bridging with a left ventricular assist device (LVAD).
Ventricular assist devices (VADs) are mechanical blood pumps that work in parallel or series with the native ventricle. A LVAD draws oxygenated blood from the left atrium or ventricle and returns it to the aorta; a right ventricular assist device (RVAD) draws venous blood from the right atrium or ventricle and returns it to the pulmonary artery.
The contexts for using mechanical circulatory support
Bridge to transplantation
Successful cardiac transplantation provided the stimulus for the development of devices that could be used to support patients until a suitable donor organ became available. The availability of donor hearts is unpredictable, hence the patient with acute haemodynamic deterioration needs other methods of circulatory support when intravenous inotropic therapy does not maintain adequate perfusion to vital organs. Renal and hepatic function improves on mechanical support, pulmonary vascular resistance falls, and nutrition and muscle strength recover. This buys time for the patient and educes the risk of subsequent transplantation. Bullet list 5 outlines guidance for use of a LVAD as a bridge to transplantation and factors affecting risk of perioperative complications.
Bullet list 5 Guidelines for the use of LVAD as a bridge to transplantation
- ◆ The patient is a candidate for transplantation, or is likely to become one with mechanical support
- ◆ Haemodynamics (usually on intravenous inotropic therapy; cardiac index <2.0 litres/min per m2; systolic blood pressure <80 mmHg; pulmonary capillary wedge pressure >20 mmHg)
- ◆ Technical—aortic regurgitation, right-to-left shunt, abdominal aortic aneurysm, prosthetic valves, left ventricular thrombus
- ◆ Severe right ventricular failure (would need BIVAD)
- ◆ Right atrial pressure >16 mmHg
- ◆ Prothrombin time >16 s
- ◆ Reoperation
- ◆ White blood cell count >15 × 109/litre; pyrexia
- ◆ Urine output <30 ml/h
- ◆ Mechanical ventilation
Depending on definition, the prevalence of severe heart failure between the ages of 65 and 75 years is 0.5 to 1.2%. Most of these patients will not be candidates for heart transplantation by virtue of age and comorbidity. VADs were originally developed as a long-term treatment for heart failure and patients who are not transplant candidates can be considered for this form of therapy.
The REMATCH study (Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure) randomized patients with endstage heart failure to best medical therapy or the implantation of the pulsatile HeartMate I assist device. Survival at 1 year was 52% in the device group and 25% in the medical group; at 2 years it was 23% and 8% respectively. Quality of life was significantly improved at 1 year in the device group, but with a higher frequency of serious adverse events. In the more recently completed HeartMate II study, patients with endstage heart failure were randomized to undergo implantation of the pulsatile HeartMate XVE or a continuous-flow LVAD (HeartMate II). The quality of life and functional capacity improved significantly in both groups. Patients implanted with the continuous-flow LVAD had superior actuarial survival rates at 2 years (58% vs 24%, p=0.008) and significantly lower adverse event rates. This provides compelling evidence that LVAD improves survival and improved quality of life in selected patients with advanced heart failure.
Bridge to recovery
Patients dying from fulminant myocarditis can be supported with mechanical circulatory support and it is not uncommon to see recovery of myocardial function to the point where the device can be removed. Recovery has also been reported in patients with idiopathic dilated cardiomyopathy. LVADs unload the ventricle to a degree that cannot be achieved by drug therapy, and there is a considerable body of evidence to show that the myocardium recovers at the cellular and molecular level with mechanical circulatory support. Structural improvement detectable by echocardiography occurs much less frequently, and clinical recovery to the point where the device can be removed safely is rarer still (<10% of patients in most series, although there are intriguing reports of higher rates of clinical recovery from a few centres). Studies are ongoing, but at present implantation of a device in patients with chronic heart failure must be viewed as a bridge to heart transplantation or as permanent support.
Several devices are available for use in patients who need support for days to periods of up to 4 to 6 weeks. These are invaluable in postcardiotomy cardiogenic shock and in patients who present in extremis with multiorgan failure. In the latter group a short-term device may be a bridge to a longer-term device or to heart transplantation, but occasionally patients may improve to the point where the device can be removed and they can be stabilized on medical therapy. This is sometimes described as "bridge to decision".
Types of VADs
There are many devices available for clinical use. Bullet list 6 shows a classification of devices and examples of each type: a brief description of selected devices in each category follows.
Bullet list 6 Classification of VADs
- ◆ Abiomed BVS 5000
- ◆ Impella
- ◆ Levitronix Centrimag
- ◆ Thoratec (PVAD and IVAD)
- ◆ HeartMate I
- ◆ Novacor
- ◆ Berlin Incor
- ◆ HeartMate II
- ◆ Jarvik 2000
- ◆ Micromed DeBakey
- ◆ Ventracor VentrAssist
- ◆ Heartware
Pulsatile devices, also referred to as volume displacement VADs, have been used for over 20 years in several thousand patients. An inflow cannula carries blood from the apex of the left ventricle to the device, while the outflow cannula connects to the ascending aorta. Porcine or mechanical valves direct blood flow in the cannulae.
Thoratec PVAD and IVAD
This device was originally used as a paracorporeal pump (PVAD), but is now also available in an implantable version (IVAD). It is the only pulsatile VAD that is designed to support either or both ventricles. It has a 65-ml stroke volume pumping chamber and produces flows of up to 7 litres/min. The implantable version has a percutaneous lead, which connects to the driver. Patients can be discharged home with the device while awaiting a transplant. Anticoagulation is required with a coumarin derivative (maintaining an INR of 2.5–3.5) and antiplatelet therapy may also be needed.
This is a vented electric implantable device that has been used in several thousand patients. The HeartMate is unique in that it has a textured inner surface that promotes a nonthrombogenic pseudoendothelium such that it is the only device for which a coumarin derivative is not required; antiplatelet therapy with aspirin is used. However, the same layer may be immunologically active and give rise to antibodies in the patient that complicate subsequent transplantation. Power is supplied by two batteries (worn on a belt) and an external controller. The two batteries supply power for 4 to 7 h. The maximum stroke volume of the pump is 83 ml and flow of between 4 and 10 litres/min can be produced. This is now largely superseded by rotary VADs.
Rotary devices deploy an impeller spinning at high speed to generate blood flow. They are smaller, have a limited blood contact surface, with a single moving part and are silent in operation. Newer pump designs have eliminated mechanical bearings altogether with the hope that these will be even more durable. Implantation is generally easier and infections are less common because of a small pump pocket and smaller drive line.
They provide continuous flow and are therefore not ‘physiological’; patients usually do not have a palpable pulse and blood pressure measurement requires Doppler devices. Rotary pumps are preload dependent and afterload sensitive. Adequate left ventricular filling is required to ensure sufficient preload to avoid ventricular "suckdown". The absence of valves makes them simpler to operate and results in less haemotrauma, but in the event of pump stoppage free regurgitation back into the ventricle may occur. Depending on native left ventricular function, some pulsatility may be seen as more blood is delivered to the pump in ventricular systole. Pump thrombosis is a potential complication of continuous flow devices and all rotary pumps currently require anticoagulation with warfarin and antiplatelet agents.
The Thoratec Heartmate II is a "second generation" device which consists of an axial-flow blood pump with a percutaneous lead that connects the pump to an external computer controller and power source. The blood pump is a 12mm diameter straight tube made of titanium alloy containing an internal rotor with helical blades that curve around a central shaft. When the rotor spins on its axis, blood is drawn from the left ventricular apex through the pump and into the ascending aorta. The pump requires a smaller pump pocket and has an implant volume of 63 ml and weighs 350 g. It operates at approximately 8,000 to 10,000 rpm and can generate up to 10 litres of flow per minute. The controller and two batteries are wearable, providing four to six hours of power. The HeartMate II has been implanted in over 5000 patients worldwide and represents the benchmark against which other continuous flow devices are being compared.
The HeartWare HVAD is a "third generation" centrifugal blood pump which contains a wide bladed impeller with a hybrid magnetic and hydrodynamic suspension. This pump only weighs 140 g, has an implant volume of 45 ml, and does not require a pump pocket, allowing intra-pericardial placement. It operates at approximately 2,000 to 3,000 rpm and can generate flows of up to 10 litres per minute. The HeartWare HVAD has been implanted in over 500 patients worldwide and has produced very favourable clinical outcomes.
Outcome of VAD Treatment
Clinical outcomes of patients treated with implantable ventricular assist devices have improved significantly over the last decade. This is a result of better understanding of patient selection criteria, the development of clinical strategies to minimise peri-operative complications, and improvements in device technology. Algorithms have been developed to risk stratify patients pre-operatively, allowing targeted medical optimisation of high risk patients prior to VAD implantation. The introduction of the INTERMACS registry in the United States created a template for rigorous data monitoring and audit. Actuarial survival following implantation of continuous flow LVADs now exceeds 90% at 6 months and 85% at 1 year. The commonest causes of 30-day mortality are cardiac failure, multi-organ failure and neurological events. In the longer-term, device related infection emerges as the most important cause of death. Multivariate analysis identified older age, greater severity of right ventricular failure, cardiogenic shock at implant, and the use of a pulsatile VAD as risk factors for death.
Complications of ventricular assist devices
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