Long-term biventricular support with rotary blood pumps: prospects and pitfalls

Congestive heart failure affects 23 million people worldwide, including 7. 5 million in North America (670 000 new cases per year) and 7 million in Europe 1. Since 10% of those over 65 suffer from systolic left ventricular dysfunction, the number of patients with heart failure will double over the next 25 years. At any time, 10% of the heart failure cohort are categorized Stage D with advanced structural heart disease and symptoms at rest, despite detailed medical and cardiac resynchronization therapy. Twenty percent of these are younger than 65 years of age (around 140 000 in both the USA and Europe). The prognosis of Stage D heart failure is grim. In the REMATCH study, only 8% of the medically treated patients were alive at 2 years and continued to suffer in the interim 2. A recurrent sentiment expressed by the Stage D patients is that they would sacrifice some duration of survival for a period of symptomatic relief 3. Cardiac transplantation provides this for a highly selected tiny minority 4. In contrast, cardiac resynchronization therapy is disappointing. A meta-analysis of 14 trials that randomized resynchronization against medical treatment showed only 59% of the NYHA IV device patients to have borderline symptomatic improvement to NYHA III with no survival benefit 5. Boyle et al. 6 compared functional outcomes for NYHA IV patients after resynchronization or implantation of a left ventricular assist device (LVAD). At 6 months, resynchronized patients achieved only an additional 6 m in the 6 min walk test (insufficient to affect their daily living) and remained NYHA III or IV. In contrast, LVAD patients improved by 341 m, achieving NYHA I or II status. The study could not be randomized because 90% of the LVAD candidates were bed-bound on intravenous inotropes and could not walk beforehand. Long-term mechanical circulatory support is an increasingly realistic ‘off the shelf’ alternative to cardiac transplantation and an effective solution for those rendered ineligible through common heart failure comorbidities 7–9. The treatment aims are uncontroversial. The first is to provide symptomatic relief and the second to achieve at least 5-year survival with a good quality of life. The third aim is cost containment by reducing the number of hospital admissions to palliate intolerable levels of breathlessness and fatigue. Hospital events account for 20. 9 billion of an overall 35 billion heart failure budget in the USA. The rationale for a blood pump deployment is clear. The failing heart beats more than 120 000 times per day pumping around 7000 l of blood against an increasing afterload. As the heart dilates, the ventricular wall tension, myocardial energy and oxygen consumption increase, while sub-endocardial blood flow decreases. The LVAD unloads the failing ventricle resulting in beneficial structural and functional changes in the diseased myocardium 10–12. Systemic blood flow returns to physiological levels to preserve the coronary and vital organ perfusion 13. When native heart contractility and segmental wall motion improve, there is less propensity for intraventricular thrombus formation and thromboembolism. In September 2011, the Society of Thoracic Surgeons and the Food and Drugs Administration (USA) assembled a ‘Think Tank’ to focus on the need for long-term mechanical circulatory support in the USA. The group acknowledged the increasing safety profile and reliability of contemporary implantable rotary blood pumps together with the potential for stem cells to broaden the horizons of heart failure management. A need for 40 000 long-term LVADs per year was predicted, which would account for 50% of the heart failure annual budget. Between 15 and 30% of patients require biventricular support and there is no satisfactory long-term mechanical solution for these patients. The pulsatile total artificial hearts have numerous restrictions which confine their use as a bridge to transplantation 14. INTERMACS data indicate that all total artificial heart patients are transplanted or dead within 6 months 15. Biventricular support is necessary when the right ventricle is severely impaired by the underlying disease process. While this seems obvious, the decision to deploy an RVAD concomitant with an LVAD implantation is very difficult. Frequently, the right heart is supported secondarily, but the staged approach conveys increased morbidity and mortality 16. The right ventricle serves to maintain low systemic venous pressure and provide flow through the lungs. It has two functionally and anatomically different cavities adapted to generate sustained low pressure perfusion through the low-resistance, high-compliance pulmonary vascular bed 17. The sinus (body) contains the tricuspid valve papillary muscles and generates systolic pressure. The pulse pressure is attenuated by the cone (outflow tract). The normal right ventricular ejection fraction is between 40 and 60%. A pulmonary perfusion pressure of 20 mm Hg permits optimum gas exchange. Elevated pressure causes histological damage to the microvasculature and eventual pulmonary hypertension. The failing right ventricle dilates to maintain the stroke volume. This remodelling disturbs the peristaltic contraction pattern, causing an accelerated rise in the pulmonary artery pressure and flow. The interventricular septum contractile function is an important determinant of the right ventricular function 18. Between 20 and 70% of the right ventricular function is derived from the left ventricle. After an LVAD implantation, global right ventricular contractility is impaired by the leftward septal shift, but the myocardial power output is maintained through a decrease in the right ventricular afterload and the elevated preload 19, 20. The pulmonary vascular resistance falls after an LVAD implantation and lower right ventricular pressure reduces the risk of dysrhythmias by decreasing the duration of monophasic right ventricular action potentials 21. Any fall in the right ventricular contractility in LVAD patients is balanced by a decreased pulmonary artery pressure (after load) secondary to a low left atrial pressure 22. An increased LVAD systemic flow boosts the venous return to the right atrium and requires increased right ventricular work 23. An acute right ventricular failure following a rotary LVAD implantation is associated with high mortality 24. Consequently, every effort should be made to determine the need for biventricular support before the LVAD insertion. A longstanding left ventricular failure with mitral regurgitation causes pulmonary hypertension, right ventricular hypertrophy and an increased right ventricular stroke work index. The trained right ventricle compensates for the increased venous return partly because the LVAD reduces the pulmonary vascular resistance 25. In contrast, a high central venous pressure with a low pulmonary artery pressure in chronic heart failure suggests impaired right ventricular function 26. In rotary LVAD patients with a mean systemic pressure of 70–90 mmHg, a high CVP reduces tissue perfusion gradient and limits the rate of hepatic renal, gastrointestinal and cerebral recovery. Numerous studies have attempted to define the preoperative pathophysiological characteristics that indicate the need for an RVAD 25–29. Although tricuspid regurgitation may reflect an elevated right ventricular afterload and remodelling, it does not necessarily indicate poor right ventricular function 30. Pulmonary hypertension and right ventricular dilatation cause an annular enlargement and secondary tricuspid regurgitation 31. When the tricuspid annulus dilates, it is the mural part that increases in length 30. The annulus becomes dilated, flattened and circular. The papillary muscle attachments arise directly from the upper septum, and are little affected by remodelling. Right atrial hypertension and a systolic reversal of flow in the vena cava are responsible for end-organ venous congestion. The regurgitant fraction also impairs the forward flow through the lungs, thereby reducing LVAD filling and the cardiac output. Uncorrected moderate or severe tricuspid regurgitation perpetuates a right ventricular dysfunction, causing progressive heart failure and a premature death. When the right ventricle fails, an increased diastolic pressure can cause a septal shift, which may impair LVAD filling 24. When the LVAD reduces the left ventricular volume, tricuspid regurgitation may be exacerbated acutely because of the leftward shift of the intraventricular septum and an increased venous return in response to the LVAD flow 32. This is an indication for a concomitant tricuspid valve repair during the LVAD insertion, not for the implantation of an RVAD 31. There is understandable reticence to complicate or prolong LVAD surgery in the high-risk heart failure patient, but tricuspid repair improves pulmonary blood flow and LVAD filling. Navia et al. 33 recently reviewed the efficacy of different types of tricuspid repair and demonstrated that a rigid prosthetic ring annuloplasty and the Kaye technique of bicuspidization by the obliteration of the mural leaflet provided a similar satisfactory long-term outcome. The Kaye technique is simple, rapid and reliable. In the Navia series, 75% of the patients with a bicuspidization commissurotomy remained free of significant tricuspid regurgitation as did 69% of the patients with a ring annuloplasty. Of the preoperative characteristics that indicate the need for an RVAD, decreased right ventricular stroke work index is probably the best. Such patients usually have hepatic and renal dysfunction and require preoperative ventilation or temporary circulatory support. The University of Pennsylvania established a risk-score model to predict which patients would require an RVAD 27. They included six variables: cardiac index ≤2. 2 l/min/m2, right ventricular stroke work index ≤0. 25 mm Hg/l/m2, severe pre-VAD right ventricular dysfunction, creatinine >1. 9 mg/dl, previous cardiac surgery and systolic blood pressure 50 predicted the need for an RVAD, the authors found a sensitivity and specificity of 83 and 80%, respectively. Investigators at the University of Michigan also established a right ventricular failure risk score derived by adding points awarded for the presence of each of the following variables: vasopressor requirement (4 points), aspartate aminotransferase (AST) >80 IU/l (2 points), bilirubin >2. 0 mg/dl (2. 5 points) and creatinine >2. 3 mg/dl (3 points) 28. In this study, patients with a score greater than 5. 5 were at a 15-fold greater risk than those with a score less than 3. 0 and about 3-fold greater risk than subjects with a score of 4. 0–5. 0 to develop right ventricular failure. Although patients deemed high risk should be considered for an RVAD, many LVAD recipients (irrespective of their risk assessment) will only declare the need for RVAD support after the LVAD has been implanted. Survival data from the HeartMate II clinical trials clearly demonstrate higher survival in patients who do not manifest right ventricular failure in response to an LVAD implantation (1-year survival 78 versus 59%) 34. Although it is clear that patients presenting with preoperative multi-organ failure require RVAD support, this should first be undertaken with a less expensive temporary system and not a long-term rotary VAD. The potential for continuous flow pumps to autoregulate themselves similar to the native heart was explored experimentally by Saxton and Andrews in 1960 35. At that time, mammalian physiology was thought to require a pulsatile blood flow and pulsatile biventricular mechanical hearts were in development. The introduction of miniaturized continuous flow pumps into the clinical arena was met with great scepticism 36. Intuitively, two small rotary blood pumps with portable power systems could be used for biventricular support. However, there are important differences between the rotary VAD performance in the pulmonary and systemic circulations. The rotary blood pump output is dependent on the speed of the rotor and the pressure difference between the inlet and outlet of the pump 37. At a fixed pump speed, an increasing gradient (higher blood pressure) decreases the flow, whereas a decreasing afterload boosts the flow. Thus, for a fixed impeller speed, the pump output will be much greater faced with pulmonary (right sided) versus systemic (left sided) vascular resistance. The power consumed by the motor rises with an increasing impeller speed and blood flow through the VAD. The power use will therefore be different for right- and left-sided VADs. The imbalance between the pulmonary and systemic flows is further exacerbated during exercise and other altered haemodynamic states. A rotary VAD will pump what is delivered to it 37. An increased preload boosts flow, and so there is inherent automated control when the intra-ventricular pressure rises during physiological stress 38. Equally insufficient preload (low blood volume) allows the pump to suck in the heart wall and obstruct. The dynamic interaction between the systemic and pulmonary VADs is also affected by anatomical issues and the fact that the volume of the venous return to the left and right atria is different 36. Between 2 and 3 ml per stroke volume (250 l per day) is distributed from the aorta to the bronchial tree but returns directly to the pulmonary veins and the left atrium. Thus, the left ventricular output is between 2 and 5% greater than the right ventricular output. Although the human heart is well adapted to accommodate the imbalance, the differences must be considered when implanting a rotary VAD in both the right and the left ventricles. Rotary VADs were initially optimized for a blood flow of 5 l per minute against a pressure of 100 mmHg. In practice, the majority of patients utilize a flow of ∼4. 5 l per min against a pharmacologically adjusted mean systemic pressure of 80 mmHg 34, 39, 40. The Berlin Heart ‘Incor’ set at 7500 rpm, will pump 3. 5 l per minute against a mean arterial pressure of 110 mmHg, versus 6. 0 l per minute against a mean pressure of 75 mmHg 41. Similarly, a Jarvik ‘FlowMaker’ set at 12 000 rpm provides a pump flow of between 3 and 6 l per minute, depending upon the high or low systemic vascular resistance during stress or sepsis 40 (Fig. 1). Plain chest X-ray of a patient with Jarvik pumps in the right and left ventricles. power is used for of There are structural differences between the rotary VADs in clinical The Berlin and HeartMate II have an between the native left ventricle and the pump 34, This as a which more blood within the left ventricular and achieve a higher left ventricular pressure The physiological response to exercise is by the pump pressure which is pulsatile when the contractility of the native ventricle The and Jarvik VADs are directly into the native left ventricle an and more the ventricle from the native left ventricle is directly through the pump to the the of an The first biventricular as a staged at the Heart in A with a Jarvik LVAD but right ventricular failure with a A second Jarvik was into the right atrium on day In the VADs provided a cardiac index with a of the central venous pressure. from sepsis and hepatic failure after 12 of biventricular support. This clinical further work to determine to the pulmonary and systemic circulations. In et al. a 75 model where both native were and with a Jarvik The pumps in any from the native accommodate the differences between the pulmonary and systemic vascular the left-sided pump was set at a speed of 14 000 rpm, while the right impeller speed was between and 12 000 The systemic blood flow was by the pulmonary blood flow and the venous return to the left atrium. The left-sided VAD was to the normal and both VADs were of the flow. The haemodynamic was optimized with right atrial and left atrial between 5 and 15 mmHg. control was used to provide and left atrial pressure of 100 15 and 15 5 mmHg, respectively. The pulmonary artery and right atrial pressure were 20 5 and 15 5 mmHg, with VAD flows between and l per The left LVAD flow was higher than the right l per of the of bronchial arterial blood to the left atrium. VADs directly to in the preload and the afterload by increasing or decreasing the flow the impeller There was no systemic or pulmonary venous congestion. This of study over 20 demonstrated that biventricular continuous flow VADs could function as a total artificial heart an atrial to accommodate an imbalance through the bronchial flow. In the the ventricular in a two HeartMate II VADs this the left impeller speed was between 000 and 15 000 with a lower right impeller speed of and 000 rpm to for the low pulmonary vascular resistance. The left impeller speed was adjusted to provide a mean blood pressure of mmHg. An in the speed of impeller an in the preload for the The increased VAD preload the flow the impeller speed remained the The for and was to a exercise the flow through both VADs the pump There was an in the total oxygen while the blood levels remained at an cardiac output this demonstrated an VAD flow pressure sensitivity which provides an automated between the systemic and pulmonary of the bronchial blood flow. The VAD preload and afterload are the of the flow and require in the clinical [36. While the impeller speed and the pressure can be in the VADs that have or mechanical Heart Jarvik HeartMate the impeller in the VAD requires a speed to maintain The speed be and to accommodate a low pulmonary vascular resistance. An alternative approach is to the to the VAD afterload. et al. this in two pumps the right and left pumps set at the speed to provide a 6 flow, a was to the right the pulmonary artery pressure to 15 mmHg. was when the mm decreased to mm Although the approach has clinical it could by of the the pressure the will when the pulmonary vascular resistance falls during the between the systemic and pulmonary is that the native heart does but pulsatile total artificial hearts do In contrast, the pressure that rotary VADs can be used for long-term biventricular support to the impeller If the VAD blood to the left atrium the left atrial pressure the left atrial pressure Thus, each VAD an important in the flow of the the systemic venous increased return to the right atrium. In with the response to exercise this causes the VAD output to as by the If the left VAD flow rate less blood is from the left atrium causing the preload to rise to maintain a flow the left and right VADs at the of their pressure flow 37. A flow is achieved a control system the biventricular system at the of hypertension or biventricular in Europe with the Jarvik and VADs of these were and are of that were not In the Berlin a with biventricular assist the (Fig. their the group that with the rotor speed of rpm, the pulmonary flow would be the mm from the right was to 5 mm for patients with a normal pulmonary vascular resistance and to mm in those with pulmonary hypertension. This was achieved by and then the over mm in length with a continuous the pump on the septum, two were to the implantation The right was then to the free wall of the right ventricle the This the between the of the and the intraventricular The left was into the of the ventricle as patients years biventricular support between September and The majority or and were INTERMACS I or II The survival was and patients were to a of to A daily of 100 was to The LVAD pump speed was set to provide the maximum flow with the left atrial pressure of mmHg. could be in a speed between and At these the provided a flow between 3. 5 and 5. 5 LVAD flows between and during the first 7 the pump speed to be adjusted to the filling of both and the of the interventricular In patient, the right flow the septum and the pump was to the right atrium. This supported for successful with pulmonary hypertension a in the pulmonary vascular resistance and a in the RVAD speed the RVAD flow the LVAD flow. Pulmonary symptoms did not In two the right ventricular function and (after and resulting in of the VAD The VADs were and the patients were with the survival of (Fig. survival was the as for the INTERMACS patients with an for support. patient has the in the of the left ventricle. has of the right ventricular free In patient the RVAD was in the right atrium. In patient with a the RVAD was through the of the right ventricle. of A patient biventricular support with the VAD. The two with control and have biventricular or staged with the with or or a lower RVAD flow rate LVAD and In following acute myocardial with ventricular septal et al. the native and with two the survival or the support duration to transplantation was months et al. demonstrated a flow during and with the LVAD output from to 7. 5 at a pump speed of rpm and the RVAD flow of to at rpm of the approach versus the fixed RVAD flow rate that provides a flow and the to the right and left circulations. There is an need for biventricular therapy. support the of rotary blood pump support in this but the important issues and A between pulmonary and systemic is because of the of these VADs but they have to at the limits of their together with the need to the of the RVAD, it less satisfactory for therapy. do not well within the of the pumps in may this there is for new to the of an LVAD as an of is and of