© 1999 European Society of Cardiology
Left ventricle assist systems: a possible alternative to heart transplantation for heart failure patients? Patient selection, techniques and benefit
Department of Cardiology and Cardiovascular Surgery ‘A. De Gasperis’, ‘Ca' Granda’ Hospital Milano-Niguarda, Italy
* Corresponding author, Programma Trapianto Cardiaco ed Insufficienza Cardiaca, Dipartimento ‘A. De Gasperis', Ospedale Niguarda-Ca’ Granda P.zza Ospedale Maggiore 3-20162 Milano, Italy. Tel.: +39-2-6444-2563; fax: +39-2-6444-2071 E-mail adderss: infodega{at}tin.it (E. Gronda)
Key Words: Left ventricle assist device • Congestive heart failure • Heart transplantation
Accepted June 25, 1999
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1. Background |
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 Top 1. Background 2. Mechanical cardiac assistance3. Patient selection4. NYHA Class IV...5. Too sick to...6. Experience at 'Ca'Granda'...7. Bridge to recoveryReferences |
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According to a survey carried out in the USA based upon reviewing the diagnoses in 5.8 million patients discharged from 800 regional hospitals in 1991 [1], the cost of treating heart failure was more than $38 billion, more than cancer or acute myocardial infarction. In spite of an overall reduction in incidence, morbidity and mortality for cardiovascular disease the number of patients with a discharge diagnosis of heart failure in the USA has doubled, reaching 750 000 cases in 1990 [2,3]. The rising prevalence of heart failure probably reflects progressive ageing of the western population and the widespread application of both cardiological and surgical interventions that rescue patients from premature death but do not provide a definitive cure. Thus, it is not surprising that heart failure is diagnosed in approximately 2.5% of the whole population aged more than 45 years [4].
Heart failure is a progressive disease and as treatments become more effective at reducing premature death advanced heart failure (AHF) becomes more prevalent. In this setting patients tend to have a similar prognosis regardless of the aetiology of their cardiac dysfunction, with a mortality of approximately 50% when symptoms become severe despite the use of conventional therapies [5].
With advancing heart failure patients become severely symptomatic at rest or with minimal physical activity and are prone to frequent episodes of cardiac decompensation requiring hospital care. A report on 3600 ambulatory patients on a heart transplant waiting list suggested that approximately 8% per month develop exacerbations requiring intensive care [6]. These patients have a very poor prognosis.
Progression of symptoms and signs may depend on the progressive activation of neuroendocrine system [7]: in fact clinical signs of heart failure become evident only when haemodynamic and neurohormonal compensatory mechanisms are overwhelmed both centrally and peripherally. Failure of medical therapy indicates that heart replacement (or assist) should be considered in suitable patients. Heart transplantation is the most definitive solution today, with a survival of over 70% after 10 years in specialised centres despite selection of very sick patients [8,9].
However, this expensive therapy has one major limitation, the scarcity of donor organs. Recent data from the International Society for Heart and Lung Transplantation on the activity of 297 institutions world-wide reported a lack of increase in the number of donors in the last 8 years, with a plateau of approximately 3500 donations/year [10]. This discouraging situation persists despite efforts to expand donor numbers by harvesting aged hearts. Older donor is more likely to have coronary disease that limits, in turn, the number that can be implanted [10]. Thus, heart transplantation alone will not be able to meet the expanding need for a cure in the majority of patients with AHF. Since heart transplantation is an option limited by organ shortage and timely availability, it seems reasonable that in this patient population the artificial heart and xenotransplantation will become alternative solutions. Xenotransplantation remains an experimental solution, but mechanical assist devices have become a reality. Patient selection and device characteristics are crucial for getting optimal results. Therefore a better understanding of the syndrome mechanisms as well as the appropriate knowledge of different devices should allow more advantageous matching between mechanical support and recipient.
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2. Mechanical cardiac assistance |
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Top1. Background2. Mechanical cardiac assistance3. Patient selection4. NYHA Class IV...5. Too sick to...6. Experience at 'Ca'Granda'...7. Bridge to recoveryReferences |
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A large number of devices are available for mechanical replacement therapy. These devices can be arbitrarily broken down into categories based on the intended length of use. These categories are short-term/acute use (hours or days), intermediate/long-term use (
29 days), and long-term/permanent use (Table 1).
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2.1. Short-term/acute devices
IABP has been used in multiple roles ranging from postcardiotomy shock to as a bridge to transplant [11]. The increased waiting period for donor hearts has limited the usefulness of this technology in the bridge situation. Centrifugal pumps were introduced in the late 1970s for use in cardiopulmonary by pass. Their use as mechanical assist devices was a logical extension of this primary function. Unfortunately, prolonged use is associated with complications including bleeding, kidney dysfunction, infection and thromboembolism [12]. ECMO, or the use of centrifugal pump in concert with an oxygenator, provides both haemodynamic and respiratory support. Poor survival and complication rates in the adult population, a limited duration support, and complication rates have caused ECMO to be used only rarely, except in the paediatric population [12] (Table 1).
2.2. Intermediate-term device
Other devices such as Thoratec and Abiomed BVS systems, are external (para-corporeal) devices that can be used not only as LVADs, but also as right ventricle assist devices (RVADs). These devices have been successfully used in the bridge-to-transplant situation and for temporary haemodynamic support in postcardiotomy shock [13]. However, these devices are subjected to the same complications as the short-term devices (Table 1).
2.3. CardioWest Total Artificial Heart (TAH)
CardioWest TAH, formerly called Jarvick or Symbiom TAH is a pulsatile pneumatic biventricular cardiac replacement system with a maximal stroke volume of 70 ml and a maximal flow rate of 15 l/min, although the average flow rate is <8 l/min on the basis of operator regulation. It is a rigid polyurethane pump containing a smooth flexible polyurethane diaphragm that separates the blood and air chambers. Two Medtronic Hall mechanical valves provide unidirectional blood flow. Compressed air from the external drive console moves the diaphragm upward pressurising the blood chamber and causing ejection of the blood.
Implantation is performed in the mediastinal space after the ventricles have been excised. Percutaneous pneumatic drive lines are attached to the drive console. Anticoagulation with warfarin, heparin, dipyridamole is necessary to prevent thrombus formation. Patients’ mobility is greatly restricted by the large drive console.
Brief intermediate and long-term support are common indications for use of this device in selected centres. Recent data show an improvement of overall results (Table 1). However, TAH may play an important role in severe biventricular failure patients with and without elevation of pulmonary vascular resistance and in those who need repeat heart transplantation [14].
2.4. Long-term/permanent devices
The most common long-term devices currently in use are the Novacor (Baxter) [15] and the Heart Mate (Thermo CardioSystem. Inc.) [16]. Both the systems are very similar with respect to function, implantation techniques and intended use: they are implanted through a median sternotomy and laparotomy, below the left hemidiaphragm just anterior to the posterior rectus muscle sheath in an intra-peritoneal or extra-peritoneal position. The device is connected by cannulas between the apex of the left ventricle. A pneumatic (pneumatic Heart Mate) or electrically powered (electrically vented Heart Mate and Novacor) mechanism compresses the blood in the device, producing forward blood flow which is directed by a pair of unidirectional mechanical or biological valves (Fig. 1a,b). Power to the device is supplied through the skin by use of an external drive line, electromechanical pumps are equipped with external rechargeable batteries that are carried on a belt and provide power for 6–8 h. These wearable systems allow patients to restart their physical activity, to leave hospital and to resume an independent lifestyle.
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Both the Novacor and Heart Mate devices support the left ventricle function alone, allowing the restoration of the right ventricle performance only by the unloading of the pulmonary circulation. As right ventricle function is not supported the performance of this cardiac chamber is crucial after implantation when the cardiac output is restored. Haemodynamic stability can be obtained with isolated left ventricle support in more than 90% of patients [17], even in those with substantial right ventricular dysfunction if left ventricle assistance is effective by reducing pulmonary hypertension. Some patients with long-standing right ventricular insufficiency have clearly a deficit of right ventricle function, moreover as a consequence of preoperative liver dysfunction right-sided heart failure patients more frequently have perioperative hemorrage [18]. Bleeding and blood transfusion activate several cytokines, tumour necrosis factor alpha can produce, through platelet activating factor, severe pulmonary hypertension [19], worsening right ventricular dysfunction.
In the past such complications required RVAD support in 20% of cases. Patients with right-sided failure with normal or low pulmonary artery pressures is a syndrome indicating severe impairment of right ventricular contractility. Perioperative use of inhaled nitric oxide to unload the right ventricle by pulmonary vasodilatation may substantially decrease the need for right ventricle mechanical support [20].
The Novacor has extensive experience in long-term support (>1 year) and the long-term reliability of the system is the strongest point for the choice of this device [15]. Heart Mate is the only device which does not require anticoagulant treatment to prevent thromboembolic events [21]. This artificial ventricle uses textured blood contacting surfaces to allow the development of a ‘pseudoneointimal’ lining that enhances bio-compatibility. Both devices can be operated in a fixed rate mode or, more often, in an automatic mode that more closely resembles normal physiologic conditions. In the automatic mode the device ejects when the pump is 90% full or when it senses a decreased rate of filling. In order to optimise the pump filling the diastole of the artificial ventricle occurs during the systole of the native ventricle while systole of the device occurs during the diastole of the native ventricle. As the patient’s activity increases the pump fills faster and the rate (or stroke volume) automatically increases pump output. With a decrease in activity, pump filling and output decrease. Both these devices allow the same sustained haemodynamic support raising the cardiac output up to 10 l/min and have similar stroke volume and maximal heart rate.
These devices are no longer responsible for significant haemolysis and the rate of infection have been significantly reduced, both implantable pneumatic/electrically vented Heart Mate and Novacor have been approved by FDA for commercial use in bridge-to-transplant cases.
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3. Patient selection |
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Top1. Background2. Mechanical cardiac assistance3. Patient selection4. NYHA Class IV...5. Too sick to...6. Experience at 'Ca'Granda'...7. Bridge to recoveryReferences |
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In acute patients too ill to be suitable for heart transplantation, such as those that cannot be weaned from cardiopulmonary by-pass, short-term para-corporeal devices are first-line therapy, although the rate of success in recovery and weaning remain discouraging [22]. However, in several cases appropriate reversion of end organs dysfunction may allow to successfully implant a long-term intracorporeal device.
Patient selection for elective implantation remains challenging. Until recently, standard criteria for the selection of patients for heart transplantation have been generally considered good guidelines for selecting patients for mechanical assist device implantation as a bridge to transplantation [23]. This is no longer accepted, especially for left ventricular long-term support as, in general, patients listed for heart transplantation and not transplanted have an overall survival at 1 year which is similar to the ones who got a new heart [24]. The key issue to maximise the cost/benefit of LVADs, is to identify the patient characteristics which predict death within the 3–4-month wait currently required for transplantation. In this population LVADs are an effective bridge to transplantation.
Although extensive use of these devices has been performed in recent years in many different institutions, clinicians are still unable to reliably predict which patients would benefit from LVAD placement. This major limitation is mainly a consequence of the continuous progression in heart failure therapy that makes AHF prognosis assessment something of a ‘moving target’.
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4. NYHA Class IV patients: the targeted population for LVADs implantation |
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Top1. Background2. Mechanical cardiac assistance3. Patient selection4. NYHA Class IV...5. Too sick to...6. Experience at 'Ca'Granda'...7. Bridge to recoveryReferences |
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Several investigators have attempted to identify categories of functional impairment and other, more objective, determinants of survival to help provide guidelines for candidate selection. A variety of other indices, such as left ventricular ejection fraction, haemodynamic profile, serum sodium and parameters of neuroendocrine activation [7,25,26], have been shown to correlate with prognosis in patients with severe heart failure, and are usually measured, but probably do not add a great deal to the fundamental categorisation of functional class in the clinical setting.
Functional class is perhaps the most widely used and recognised prognostic factor in patients with advanced heart disease. In a controlled trial using more modern therapy (the CONSENSUS trial using digoxin, diuretics, angiotensin converting enzyme inhibitors and in many cases other vasodilators) [5], 1-year survival of Class IV patients was approximately 60%.
When symptoms progress and patients become symptomatic at rest, particularly when oral therapy is poorly tolerated the short-term outcome is ominous [27–30]. ACE-inhibitors and beta-blockers interfere with compensatory mechanisms, such as the increase in systemic vascular resistance and in the heart rate, that may be required to sustain the circulation in severely decompensated heart failure. Intravenous inotropic agents may become necessary to stabilise patients in the effort to put them back on oral therapy. In order to prevent frequent hospital re-admissions there is some evidence that intermittent infusion of inotropic agents (i.e. dobutamine, milrinone or enoximone 24–48 h/week) successfully limits acute decompensation allowing the patient to leave the hospital and to wait until a donor is available [29,30]. However, intermittent infusion of inotropic agents do not allow physical re-conditioning, but LVADs do [31] facilitating hospital discharge, increasing the patient’s capacity to engage in other activities including driving and, sometimes, allowing patients to return to work. In other words LVADs can restore some patients to a near-normal life style.
It is noteworthy that the need for prolonged inotropic support, despite correct weaning attempts (i.e. appropriate fluid balance and vasodilating therapy), clearly entails a failure of medical therapy, intense activation of neuro-endocrine and cytokine systems, oxidative stress, portending death unless the patient is transplanted [32–36].
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5. Too sick to get benefit |
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Top1. Background2. Mechanical cardiac assistance3. Patient selection4. NYHA Class IV...5. Too sick to...6. Experience at 'Ca'Granda'...7. Bridge to recoveryReferences |
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Device implantation should improve peripheral blood flow, reduce the haemodynamic load on the ventricle but must avoid an excessive burden of complication related to the surgical procedure which is difficult to bear when severe end organ damage is present or general condition too poor, such as in the end stage of AHF syndrome with cachexia. Cachexia, indeed, is a marker of the last step progression of long-standing heart failure [37].
In this clinical setting, poor nutrition, skeletal muscle, kidney, liver, CNS and lung damage together with activation of inflammatory response make recovery from major surgery difficult. Such patients become more prone to bleeding, infection, acute respiratory distress syndrome, etc., which exacerbate or precipitate multi-organ failure and hinder peri-operative recovery. Recipient age and other associated medical conditions such as diabetes and major neurologic deficits will also influence outcome.
Renal dysfunction requiring haemodialysis is an absolute contraindication to LVAD implantation, but moderate renal dysfunction is not, and can improve or even disappear with the restoration of adequate cardiac output, while ultrafiltration can help to manage fluid retention before and post LVAD implantation.
Preoperative liver insufficiency with prolonged prothrombin time is frequent in right heart failure. Aggressive medical treatment which can restore nearly normal liver synthesis is warranted. The persistence of a prolonged prothrombin time of over 16 s usually contraindicates device implantation [38].
Significant preoperative infection is a contraindication to device implantation, not only because of the risk of device infection and septicaemia, but also because it may elicit a more intense inflammatory response with a detrimental effect on haemostatic balance, enhancing the risk related both to bleeding after and to clot formation. Severe aortic arch calcification can prevent optimal anastomosis of the outflow conduit as can arterial and aorto-iliac disease, which can complicate arterial cannulation. A number of other absolute contraindications to LVAD implantation exist. These include technical issues, such as small body surface area (<1.5 m2): having the need to place the device beneath the abdominal wall, it can affect the outcome causing excessive disrupting force on the wound.
Other physiological problems including significant aortic regurgitation or mitral stenosis, or factors which can preclude a patient from being candidate to heart transplantation are to be considered as contraindications. In the REMATCH trial, some contraindications such as previous malignancy, may not be an absolute contraindication but are weighed in relation to the expected survival and the likelihood that the LVAD would function appropriately for longer than this period.
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6. Experience at ‘Ca’Granda’ General Regional Hospital, Milano-Niguarda |
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Top1. Background2. Mechanical cardiac assistance3. Patient selection4. NYHA Class IV...5. Too sick to...6. Experience at 'Ca'Granda'...7. Bridge to recoveryReferences |
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Mechanical assist device implantation started in 1988 at ‘Ca’Granda’ Hospital, Milano-Niguarda, 3 years after the beginning of the Heart Transplant Program. Table 2 summarises the results of the activity until May 1999; two time periods are addressed. The first era (1988–1995) was mainly characterised by support implant in 20 patients, seven had a BVAD implant and most of this cohort were mortally ill.
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In the second era (1995–present) there was a shift towards severely ill patients but with fewer emergency cases. The decision for implant was based more on failure of medical treatment (e.g. need for prolonged inotropic support, 2 weeks or more, fluctuating end organ damage, etc.) than to the immediate risk of death. In this era the patient cohort had only LVAD implant with an increase in the average duration of the support and in the number of long-term survivors.
These data are consistent with the hypothesis that LVAD implant should be considered as an alternative to medical treatment when drugs administration does not obtain a stable clinical setting.
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7. Bridge to recovery |
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Top1. Background2. Mechanical cardiac assistance3. Patient selection4. NYHA Class IV...5. Too sick to...6. Experience at 'Ca'Granda'...7. Bridge to recoveryReferences |
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The mechanical unloading afforded by the LVAD may result in attenuation of the myocardial histologic abnormalities caused by chronic heart failure, including normalization of fibre orientation, regression of myocyte hypertrophy and in contraction band necrosis. Prolonged left ventricular unloading reverses ventricular dilatation, as demonstrated by an improvement in the end-diastolic pressure–volume relation. Long-term support with an LVAD improves the efficiency of myocardial mitochondria and results in a reduction of neuroendocrine activation that accompanies heart failure. Many centres have reported patients with LVAD whose myocardial function improved enough to allow removal of the device, where previously a heart transplant had been considered necessary, a scenario now termed a ‘bridge to myocardial recovery’.
In this clinical arena a key role is played by the cross-talk between basic science and clinical practice. This is facilitated by following these patients in a dedicated Heart Failure Unit, in order to optimise the use of health care resources and to verify new management algorithms. Once these become validated, it becomes possible to extend their application to the wider population of patients with heart failure seen in non-specialised hospitals.
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References |
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