Article

Left Ventricular Assist Devices in the Management of Heart Failure

Abstract

Mechanical circulatory support has emerged as an important therapy for advanced heart failure, with more than 18,000 continuous flow devices implanted worldwide to date. These devices significantly improve survival and quality of life and should be considered in every patient with end-stage heart failure with reduced ejection fraction who has no other life-limiting diseases. All candidates for device implantation should undergo a thorough evaluation in order to identify those who could benefit from device implantation. Long-term management of ventricular assist device patients is challenging and requires knowledge of the characteristic complications with their unique clinical presentations.

Disclosure: Edo Y. Birati received research and fellowship support from HeartWare Ltd. Mariell Jessup has no relevant disclosures.

Received:

Accepted:

Correspondence: Mariell Jessup, MD, Hospital of the University of Pennsylvania, 2 East Perelman Pavilion, 3400 Civic Center Boulevard, Philadelphia, PA 19104, US. E: jessupm@uphs.upenn.edu

Open access:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide, affecting 1–2 % of the adult population in western countries with incidence of 5–10 per 1000 persons per year.1,2 It is estimated that the prevalence of HF will continue to increase as the population ages and, according to the American Heart Association (AHA), by the year 2030 the prevalence of HF in the US alone will rise to over 8 million patients, representing a 25 % increase compared to the
year 2010.3 HF is one of the common causes for hospitalisation, representing 1–2 % of all hospital admissions and the leading reason for admission in individuals above 65 years of age.4–6

HF is a progressive disease7 with approximately 5 % of HF patients suffer from end-stage disease refractory to medical therapy.8,9 The Heart Failure Association of the European Society of Cardiology (ESC) defined advanced HF as a state in which patients have significant cardiac dysfunction with severe HF symptoms, such as dyspnoea and/or fatigue, occurring at rest or with minimal exertion (NYHA functional class III or IV) despite maximal medical and device (cardiac resynchronisation therapy) therapy.10 In addition to the aforementioned symptoms, patients with advanced HF usually have objective measurements of peak VO2 (oxygen uptake) <14mL/kg/min, a 6-minute walk distance <300 meters, and poor cardiac function.10,11 The prognosis of patients with advanced HF is dismal, with life expectancy of less than two years.11,12 At this stage, advanced therapies are considered, including heart transplantation, continuous inotropic therapy, mechanical circulatory support or hospice.1,10,11 Heart transplantation remains the preferable therapy for advanced HF, but the number of transplants done worldwide is trivial compared to demand.13 Thus, durable mechanical circulatory support (MCS) devices have emerged as an important therapy for advanced HF.13,14
To date, over 18,000 continuous flow devices have been implanted worldwide.13,14 In the US alone, 131 hospital centres are approved to implant permanent MCS devices, demonstrating the staggering expansion of MCS as a therapeutic option for end-stage HF.15

The Nomenclature of MCS

A ventricular assist device (VAD) is a MCS device that is used to partially or completely support the function of a failing heart. Left ventricular assist devices (LVAD) pump blood from the left ventricle and transfer it to the ascending aorta. LVADs may be used as a bridge to transplant (BTT) for candidates awaiting heart transplantation; as destination therapy (DT) for patients who are not candidates for transplantation; as a bridge to decision for patients too sick to survive the transplant evaluation (so that their suitability for transplantation has not been determined at the time of VAD implantation) and as a bridge to recovery for selected patients who might recover their cardiac function. The latter patients are mostly those with acute cardiomyopathies (ie. fulminant lymphocytic myocarditis, peripartum cardiomyopathy, etc).11 Interestingly, according to the Sixth annual report of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) the proportion of patients treated with LVAD as DT in the United Sates has increased from 14.7 % in 2006–7 to 41.6 % in 2011–13.14

The first-generation VADs had pulsatile flow, designed to mimic the normal function of the heart. These devices were shown to increase survival and quality of life (QoL) of patients with end-stage HF compared to optimal medical therapy (OMT).16 The second and third generation devices currently in use (primarily HeartMate II, Thoratec Corp. and HVAD, HeartWare Ltd., see Figure 1), have continuous flow patterns, and can generate up to 10 litres/minute. Although these devices generate continuous flow, pulsatility may still be present in some patients since the flow delivered by the device is modified by native left ventricular (LV) contractility. Nevertheless, some studies suggest that pulsatile flow is not necessary for adequate perfusion of the end organs.17

In the ‘HeartMate II’ trial, treatment with continuous-flow HeartMate II devices as DT was associated with improved survival compared to

treatment with continuous-flow HeartMate II devices as DT was associated with improved survival compared to

Article image

Table 1: American Heart Association Recommendations for Mechanical Circulatory Support

Article image

pulsatile-flow devices.18 In addition, patients treated with continuous flow-devices as DT had a significant reduction in the rate of adverse events and hospitalisations and had improved QoL and functional capacity compared to patients treated with pulsatile-flow devices.18
To evaluate whether ‘real life’ outcomes are similar to those observed in the clinical trials, Jorde et al.19 followed the first 247 patients treated with HeartMate II devices as DT who were not in a clinical trial and compared their outcome with those achieved
in the clinical trials. Survival in the later group trended to be better than in the initial clinical trial, with an absolute difference of 74 % versus 68 % at 1 year and 61 % versus 58 % at 2 years (p=0.2). Moreover, the rate of survival free of stroke (both haemorrhagic and ischaemic), device-related infection, or pump replacement was significantly higher in patients treated in the later group.19 These results are consistent with the outcomes summarised in the
Sixth INTERMCAS annual report of 80 % 1-year survival and 70 % 2-year survival.14

Treatment with the HeartWare HVAD device as a bridge to transplantation (BTT) was evaluated in the ADVANCE (HeartWare Ventricular Assist Device Bridge to Transplant) trial.20 In this study, the HeartWare HVAD device was compared to ‘commercially available devices’, mainly HeartMate II, in patients awaiting heart transplantation. The HVAD device was non-inferior to the HeartMate device with 1-year survival of 86 % and enhanced QoL and functional capacity similar to what was seen with the HeartMate II.20 The safety and effectiveness of HeartWare HVAD as DT is being evaluated in the ENDURANCE trial, yet to be published.

Patient Selection

LVAD therapy should be considered in every patient with end-stage systolic (low LV ejection fraction) HF who has no other life-limiting diseases. Tables 1 and 2 summarise the current MCS recommendation from the AHA and the ESC. Table 3 details the indications and contraindication for MCS.

A MCS evaluation is essential to identify those patients who could benefit from device implantation, and to exclude those considered futile for device therapy. The first step in patient selection is to accurately estimate the clinical severity of the HF syndrome. Many US clinicians22 recommend the use of two prognostic scores, the Heart Failure Survival Score23 and the Seattle Heart Failure Model,24 to estimate the expected two-year survival on medical therapy in candidates who might benefit from LVAD support.22 The ESC recommend assessing the patient’s prognosis using variables that have been shown to predict outcome, such as findings in history and physical examination (NYHA class, blood pressure, signs of congestions, etc.), laboratory tests (serum sodium, liver enzymes, troponins, etc.), neuro-hormonal activity (Plasma renin activity, Angiotensin II, etc.), and functional (peak VO2) and haemodynamic variables.10,21 Likewise, it is now apparent that there are many phenotypes of advanced HF, which have been described with the INTERMACS profiles, a classification of 7 clinical profiles (see Table 4).25 Patients with INTERMACS profile 1 to 3 are being managed with temporary mechanical or inotropic support, whereas patients with profile 4 to 7 are not inotrope dependent.11,25 The INTERMACS profiles have been shown to provide prognostic information and guidance for the optimal timing and the associated risk of implantation.26,27 For example, INTERMACS profile 1 or 2 patients who are treated with LVAD have a 44 % higher post-implantation mortality than that of patients at INTERMACS profile 3 or 4.27 In addition, several risk scores have been developed for the estimation of short-term mortality after LVAD implantation.11,22 The ‘Lietz-Miller score’ was the most frequently used risk score for DT patients (see Table 5)28, but is now limited in use as it was developed on the first generation HeartMate XVE device.28

Table 2: European Society of Cardiology Recommendations For Mechanical Circulatory Support

Article image

Table 3: Indication and Contra-indication for Durable Mechanical Circulatory Support

Article image

The second step in the evaluation is to search for significant co-morbidities and other factors that might limit the patient’s suitability.11 This search should include the possibility of reversible causes of heart failure (for example: obstructive sleep apnoea), metabolic stress testing when feasible (stress tests are contra-indicated in patients on inotropes), invasive haemodynamic evaluation, laboratory evaluation of organ function including lungs (pulmonary function tests), renal, liver, and haematologic function. All patients should undergo a psychosocial evaluation to estimate patient psychological status, risk for substance abuse, compliance to treatment and
supporting environment.22,29

Right ventricular (RV) failure is a leading cause of mortality after LVAD implantation,22 since LVAD optimal function relies on adequate filling of the left ventricle (LVAD preload), which in turn is dependent on RV function. Many studies have tried to predict which patients are at risk for RV failure after LVAD implantation.30–36 Table 6 summarises the major published predictors of post implant RV failure.

The final step in evaluating LVAD candidates is an estimation of a patient’s overall frailty. Frailty was originally a geriatric term defined

Table 4: INTERMACS Profiles

Article image

Table 5: Risk Factors for Post-implant 90-Day Survival The Lietz Model

Article image

as a state of vulnerability to adverse outcomes and decreased physiologic reserve, reflecting the biologic rather than chronologic age.37,38 Frailty is very common among HF patients and adversely affects prognosis39,40. In LVAD patients, frailty is associated with higher post-implant complication rates and mortality.38,41

LVAD Complications

Patients treated with long-term MCS may develop characteristic complications associated with the implantation of the VAD.

VAD Thrombosis

VAD thrombosis, one of the most devastating complications of MCS, is defined as the development of a blood clot within one component of the device, including the inflow cannula, outflow cannula, and the rotor despite anticoagulation and antiplatelet therapy.42 Since 2011, for unknown reasons, there has been a reported abrupt increase in the incidence of HeartMate II VAD thrombosis from 2.2 % before 2011 to 8.4 % in 2013.42 Device thrombosis is also a complication in

Table 6: Pre-implant Predictors of Acute Right Ventricle Failure

Article image

HeartWare HVAD devices, reported to occur in 8.1 % of the patients.43 However, unlike the increase in the incidence of HeartMate II VAD thrombosis, the incidence of HeartWare HVAD thrombosis has remained stable since 2008.43,44 With the growth in the number of patients treated with LVAD, the magnitude of this complication will continue to rise if there is no deployable strategy to mitigate the risk of pump thrombosis.45

VAD thrombosis has more than one clinical presentation, and can involve a wide spectrum of clinical features, ranging from an asymptomatic patient to one with refractory cardiogenic shock and subsequent death.45 The various clinical presentations are detailed in Figure 2. Even early stages of VAD thrombosis may cause haemolysis that can be identified with elevated lactate dehydrogenase (LDH) levels, indirect bilirubin and plasma free haemoglobin (PFHg) levels.22 Uriel et al.46 reported that an LDH higher than five times normal was 100 % sensitive and 92 % specific for the diagnosis of pump thrombosis46, but our series argue that any value above the normal LDH range can imply VAD thrombosis.45

Patients with a suspected diagnosis of VAD thrombosis should be started on intravenous heparin, unless contraindicated; patients with highly suspected VAD thrombosis should be considered for pump exchange.47 Starling et al.42 showed that the six-month mortality of HeartMate II patients treated with device replacement was similar to the mortality of patients who did not have pump thrombosis.42 In patients with HeartWare HVAD thrombosis it is reasonable to start thrombolysis if the patient is haemodynamically stable and has no contraindications for thrombolytic therapy. However, if the HVAD patient does not improve clinically or suffer from haemodynamic instability, pump replacement should be considered.47

Acute Right Ventricular Failure

Acute RV failure is a frequent complication, occurring in 20–50 % of patients following LVAD implantation, and is associated with increased morbidity and mortality.48–50 Acute RV failure post-LVAD implantation is defined as a need for inotropes longer than 14 days after LVAD implant or the need for temporary RVAD placement after LVAD surgery.48,51

Figure 2: The Clinical Presentation of Ventricular Assist Device Thrombosis

Article image

After LVAD placement, there is an abrupt decrease in the left ventricular end-diastolic pressure (LVEDP), followed by a decrease in left pulmonary capillary wedge pressure. In most patients this, in turn, causes a decrease in the pulmonary vascular resistance (PVR), thus decreasing the afterload of the right ventricle.52 However, some patients have a significant shift of the inter-ventricular septum towards the LV secondary to the decrease in the LVEDP and LV size and consequently an increase in RV preload. This shift of the septum adversely affects the function of the RV. High device speeds enhance this inter-ventricular septum shift, and can further deteriorate the RV function. Thus, it is highly recommended to conduct repeat echocardiographic studies during the first days after the implantation and to adjust the pump speed according to the septal movement and the ventricles size. RV failure can result in inadequate filling of the LV. Since the LVAD is preload dependent, patients with acute RV failure may present with cardiogenic shock.

Up to 15 % of patients with acute RV failure will require RVAD implantation.53 These patients suffer from severe RV failure leading to end organ dysfunction and cardiogenic shock refractory to inotropes.53

In an effort to prevent RV failure, some authors advocate for the routine use of phosphodiesterase type 5 inhibition, nitric oxide, or Epoprostenol Sodium (Flolan) therapy in every patient with pre-implant PVR above 3.11

Gastrointestinal Bleeding

Approximately one forth of VAD patients suffer from gastrointestinal bleeding (GI)54; half of the bleeding episodes originate from the upper GI tract. Although angiodysplastic lesions are the predominant cause of bleeding, stress and peptic ulcers are common in this patient population as well.54

The increased risk of bleeding is associated with several factors. First, similar to the Heyde syndrome of aortic stenosis, LVAD rotors generate high shearing forces leading to degradation of von Willebrand factor and acquired von Willebrand syndrome.55–57 Second, the continuous-flow devices generate low pulse pressures, which may cause GI hypoperfusion leading to formation of angiodysplastic lesions.58 In addition, most VAD patients are treated regularly with anticoagulation and antiplatelet regimens, which further increases the risk of bleeding.54 Figure 3 summarises the recommended treatment strategy of GI bleeding.59

Infection and Sepsis

Infection is a major cause for morbidity and mortality in LVAD
patients. Although the prevalence of VAD associated infections is improving with second and third generation devices, it continues to be a worrisome complication, with 20 % of VAD deaths attributed
to infection.60,61

According to the International Society of Heart and Lung Transplantation (ISHLT) data, 87 % of VAD infections are bacterial (primarily Staphylococcus and Pseudomonas species) with the reminder being mostly fungal.62,63 The clinical presentation of VAD infections may be nonspecific and misleading, with symptoms such as lethargy, fatigue, or anorexia, with or without fever or shock.64 Table 7 summarises the ISHLT Infectious Diseases Working Group definition of infection in VAD patients.

Driveline infections are the most prevalent infections in VAD patients and may reflect the presence of a deeper infection of the device hardware (pump, cannula) or the pocket space. Due to the marked variability in the clinical presentation, vigilance is required for an early diagnosis of infection.

The Future of Ventricular Assist Device Therapy

The surge in the prevalence of HF worldwide will result in a substantial rise in the number of patients treated with long-term MCS. The next generation devices are currently being evaluated in clinical trials. These devices are smaller and easier to implant. Moreover, they are designed to have more flexible percutaneous leads, in an effort to decrease the risk of infections.65,66 Future devices will be more physiologic and will be able to automatically accommodate
to the patient’s physical activity and position. In addition, devices in the future will have trans-dermal charging so that the system is totally within the body, which will further decrease the risk of infection, and allow patients to swim and shower with no limitation on daily activities.

Table 7: ISHLT Infectious Diseases Working Group definition of infection in VAD patients

Article image

Figure 3: Treatment Strategy of GI Bleeding

Article image

With the accumulating experience and improved outcomes, it is likely that the indications for LVAD implantation will expand and include patients with less severe HF. Finally, there is an ongoing interest in treating HF patients with preserved LVEF with durable MCS.67

In conclusion, MCS has emerged as an essential option for advanced HF, with increasing number of patients treated with this modality. These devices significantly improve survival and quality of life in appropriately selected patients. Awareness of the unique complications and clinical presentations is crucial for the long-term management of VAD patient

References

  1. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013;128:1810–52.
    Crossref | Pubmed
  2. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart. 2007;93:1137–46.
    Crossref | Pubmed
  3. Albert NM, Allen LA, Bluemke DA, et al. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail 2013;6:606–19.
    Crossref | Pubmed
  4. Blecker S, Paul M, Taksler G, et al. Heart failure–associated hospitalizations in the United States J Am Coll Cardiol, 2013;61:1259–67.
    Crossref | Pubmed
  5. Parissis J, Athanasakis K, Farmakis D, et al. Determinants of the direct cost of heart failure hospitalization in a public tertiary hospital. Int J Cardiol 2015;180:46–9.
    Crossref | Pubmed
  6. Lloyd-Jones D, Adams RJ, Brown TM, et al. Heart disease and stroke statistics—2010 update. A report from the American Heart Association Statistics. Circulation 2010:121:e46–215.
    Crossref | Pubmed
  7. Jessup M, Brozena S. Heart failure. N Engl J Med 2003;348:2007–18.
    Crossref | Pubmed
  8. Costanzo MR, Mills RM, Wynne J. Characteristics of “stage D” heart failure: insights from the Acute Decompensated Heart Failure National Registry Longitudinal Module (ADHERE LM). Am Heart J 2008;155:339–47.
    Crossref | Pubmed
  9. Adler ED, Goldfinger JZ, Kalman J, et al. Palliative care in the treatment of advanced heart failure. Circulation 2009;120:2597–606.
    Crossref | Pubmed
  10. Metra M, Ponikowski P, Dickstein K, et al. Advanced chronic heart failure: A position statement from the Study Group on Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2007;9:684–94.
    Crossref | Pubmed
  11. Peura JL, Colvin-Adams M, Francis GS, et al. Recommendations for the use of mechanical circulatory support: device strategies and patient selection: a scientific statement from the American Heart Association. Circulation 2012;126:2648–67.
    Crossref | Pubmed
  12. Birati EY, Rame JE. Left ventricular assist device management and complications. Crit Care Clin 2014;30:607–27.
    Crossref | Pubmed
  13. Birati EY, Rame JE. Post-heart transplant complications. Crit Care Clin 2014;30:629–37.
    Crossref | Pubmed
  14. Kirklin JK, Naftel DC, Pagani FD, et al. Sixth INTERMACS annual report: a 10,000-patient database. J Heart Lung Transplant 2014;33:555–64.
    Crossref | Pubmed
  15. Patel CB, Cowger JA, Zuckermann A. A contemporary review of mechanical circulatory support. J Heart Lung Transplant 2014;33:667–74.
    Crossref | Pubmed
  16. Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med 2001;345:1435–43.
    Crossref | Pubmed
  17. Sayer G, Naka Y, Jorde UP. Ventricular assist device therapy. Cardiovasc Ther 2009;27:140–50.
    Crossref | Pubmed
  18. Slaughter MS, Rogers JG, Milano CA, et al. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 2009;361:2241–51.
    Crossref | Pubmed
  19. Jorde UP, Kushwaha SS, Tatooles AJ, et al. Results of the destination therapy post-food and drug administration approval study with a continuous flow left ventricular assist device: a prospective study using the INTERMACS registry (Interagency Registry for Mechanically Assisted Circulatory Support). J Am Coll Cardiol 2014;63:1751–7.
    Crossref | Pubmed
  20. Aaronson KD, Slaughter MS, Miller LW, et al. Use of an intrapericardial, continuous-flow, centrifugal pump in patients awaiting heart transplantation. Circulation 2012;125:3191–200.
    Crossref | Pubmed
  21. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787–847.
    Crossref | Pubmed
  22. Slaughter MS, Pagani FD, Rogers JG, et al. Clinical management of continuous-flow left ventricular assist devices in advanced heart failure. J Heart Lung Transplant 2010;29(4 Suppl):S1–39.
    Crossref | Pubmed
  23. Aaronson KD, Schwartz JS, Chen TM, et al. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 1997;95:2660–7.
    Crossref | Pubmed
  24. Levy WC, Mozaffarian D, Linker DT, et al. The Seattle heart failure model: prediction of survival in heart failure. Circulation 2006;113:1424–33.
    Crossref | Pubmed
  25. Stevenson LW, Pagani FD, Young JB, et al. INTERMACS profiles of advanced heart failure: the current picture. J Heart Lung Transplant 2009;28:535–41.
    Crossref | Pubmed
  26. Alba AC, Rao V, Ivanov J, et al. Usefulness of the INTERMACS scale to predict outcomes after mechanical assist device implantation. J Heart Lung Transplant 2009;28:827–33.
    Crossref | Pubmed
  27. Boyle AJ, Ascheim DD, Russo MJ, et al. Clinical outcomes for continuous-flow left ventricular assist device patients stratified by pre-operative INTERMACS classification. J Heart Lung Transplant 2011;30:402–7.
    Crossref | Pubmed
  28. Lietz K, Long JW, Kfoury AG, et al. Outcomes of left ventricular assist device implantation as destination therapy in the post-REMATCH era: implications for patient selection. Circulation 2007;116:497–505.
    Crossref | Pubmed
  29. Halbreiner MS, Soltesz E, Starling R, Moazami N. Current Practice in Patient Selecting for Long-Term Mechanical Circulatory Support. Curr Heart Fail Rep 2015;12(2):120–9.
    Crossref | Pubmed
  30. Matthews JC, Koelling TM, Pagani FD, Aaronson KD. The right ventricular failure risk score a pre-operative tool for assessing the risk of right ventricular failure in left ventricular assist device candidates. J Am Coll Cardiol 2008;51:2163–72.
    Crossref | Pubmed
  31. Grant ADM, Smedira NG, Starling RC, Marwick TH. Independent and incremental role of quantitative right ventricular evaluation for the prediction of right ventricular failure after left ventricular assist device implantation. J Am Coll Cardiol 2012;60:521–8.
    Crossref | Pubmed
  32. Raina A, Seetha Rammohan HR, Gertz ZM, et al. Postoperative right ventricular failure after left ventricular assist device placement is predicted by preoperative echocardiographic structural, hemodynamic, and functional parameters. J Card Fail 2013;19:16–24.
    Crossref | Pubmed
  33. Kiernan MS, French AL, DeNofrio D, et al. Preoperative Three Dimensional Echocardiography to Assess Risk of Right Ventricular Failure Following Left Ventricular Assist Device Surgery. J Card Fail. 2015;21:189–97.
    Crossref | Pubmed
  34. Ochiai Y, McCarthy PM, Smedira NG, et al. Predictors of severe right ventricular failure after implantable left ventricular assist device insertion: analysis of 245 patients. Circulation 2002;106:I198–202.
    Pubmed
  35. Schenk S, McCarthy PM, Blackstone EH, et al. Duration of inotropic support after left ventricular assist device implantation: risk factors and impact on outcome. J Thorac Cardiovasc Surg 2006;131:447–54.
    Crossref | Pubmed
  36. Kormos RL, Teuteberg JJ, Pagani FD, et al. Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device: incidence, risk factors, and effect on outcomes. J Thorac Cardiovasc Surg 2010;139:1316–24.
    Crossref | Pubmed
  37. Afilalo J, Karunananthan S, Eisenberg MJ, et al. Role of frailty in patients with cardiovascular disease. Am J Cardiol 2009;103:1616–21.
    Crossref | Pubmed
  38. Dunlay SM, Park SJ, Joyce LD, et al. Frailty and outcomes after implantation of left ventricular assist device as destination therapy. J Heart Lung Transplant 2014;33:359–65.
    Crossref | Pubmed
  39. Cacciatore F, Abete P, Mazzella F, et al. Frailty predicts long-term mortality in elderly subjects with chronic heart failure. Eur J Clin Invest 2005;35:723–30.
    Crossref | Pubmed
  40. Lupon J, Gonzalez B, Santaeugenia S, et al. Prognostic implication of frailty and depressive symptoms in an outpatient population with heart failure. Rev Esp Cardiol 2008;61:835–42.
    Crossref | Pubmed
  41. Chung CJ, Wu C, Jones M, et al. Reduced handgrip strength as a marker of frailty predicts clinical outcomes in patients with heart failure undergoing ventricular assist device placement. J Card Fail 2014;20:310–5.
    Crossref | Pubmed
  42. Starling RC, Moazami N, Silvestry SC, et al. Unexpected abrupt increase in left ventricular assist device thrombosis. N Engl J Med 2014;370:33–40.
    Crossref | Pubmed
  43. Aaronson KD, Slaughter MS, Miller LW, et al. Use of an intrapericardial, continuous-flow, centrifugal pump in patients awaiting heart transplantation. Circulation 2012;125:3191–200.
    Crossref | Pubmed
  44. Najjar SS, Slaughter MS, Pagani FD, et al. An analysis of pump thrombus events in patients in the HeartWare ADVANCE bridge to transplant and continued access protocol trial. J Heart Lung Transplant 2014;33:23–34.
    Crossref | Pubmed
  45. Birati EY, Quiaoit Y, Wald J, et al. Ventricular assist device thrombosis: A wide spectrum of clinical presentation. J Heart Lung Transplant 2014 Dec 24 [Epub ahead of print]
    Crossref | Pubmed
  46. Uriel N, Morrison KA, Garan AR, et al. Development of a novel echocardiography ramp test for speed optimization and diagnosis of device thrombosis in continuous-flow left ventricular assist devices: the Columbia ramp study. J Am Coll Cardiol 2012;60:1764–75.
    Crossref | Pubmed
  47. Birati EY, Rame JE. Diagnosis and Management of LVAD Thrombosis. Curr Treat Options Cardiovasc Med 2015;17:361.
    Crossref | Pubmed
  48. Meineri M, Van Rensburg AE, Vegas A. Right ventricular failure after LVAD implantation: prevention and treatment. Best Pract Res Clin Anaesthesiol 2012;26:217–29.
    Crossref | Pubmed
  49. Dang NC, Topkara VK, Mercando M, et al. Right heart failure after left ventricular assist device implantation in patients with chronic congestive heart failure. J Heart Lung Transplant 2006;25:1–6.
    Crossref | Pubmed
  50. Morgan JA, John R, Lee BJ, et al. Is severe right ventricular failure in left ventricular assist device recipients a risk factor for unsuccessful bridging to transplant and post-transplant mortality. Ann Thorac Surg 2004;77:859–63.
    Crossref | Pubmed
  51. Morgan JA, Paone G, Nemeh HW, et al. Impact of continuous-flow left ventricular assist device support on right ventricular function. J Heart Lung Transplant 2013;32:398–403.
    Crossref | Pubmed
  52. Atluri P, Fairman AS, MacArthur JW, et al. Suarez Continuous flow left ventricular assist device implant significantly improves pulmonary hypertension, right ventricular contractility, and tricuspid valve competence. J Card Surg 2013;28:770–5.
    Crossref | Pubmed
  53. MacGowan GA, Schueler S. Right heart failure after left ventricular assist device implantation: early and late. Curr Opin Cardiol 2012;27:296–300.
    Crossref | Pubmed
  54. Draper KV, Huang RJ, Gerson LB. GI bleeding in patients with continuous-flow left ventricular assist devices: a systematic review and meta-analysis. Gastrointest Endosc 2014;80:435–46.
    Crossref | Pubmed
  55. Uriel N, Pak SW, Jorde UP, et al. Acquired von Willebrand syndrome after continuous-flow mechanical device support contributes to a high prevalence of bleeding during long-term support and at the time of transplantation. J Am Coll Cardiol 2010;56:1207–13.
    Crossref | Pubmed
  56. Klovaite J, Gustafsson F, Mortensen SA, et al. Severely impaired von Willebrand factor-dependent platelet aggregation in patients with a continuous-flow left ventricular assist device (HeartMate II). J Am Coll Cardiol 2009;53:2162–7.
    Crossref | Pubmed
  57. Bartoli CR, Restle DJ, Zhang DM, et al. Pathologic von Willebrand factor degradation with a left ventricular assist device occurs via two distinct mechanisms: Mechanical demolition and enzymatic cleavage. J Thorac Cardiovasc Surg 2015;149:281–9.
    Crossref | Pubmed
  58. Demirozu ZT, Radovancevic R, Hochman LF, et al. Arteriovenous malformation and gastrointestinal bleeding in patients with the Heart- Mate II left ventricular assist device. J Heart Lung Transplant 2011;30:849–53.
    Crossref | Pubmed
  59. Suarez J, Patel CB, Felker GM, et al. Mechanisms of bleeding and approach to patients with axial-flow left ventricular assist devices [review]. Circ Heart Fail 2011;4:781.
    Crossref | Pubmed
  60. Holman WL, Park SJ, Long JW, et al. Infection in permanent circulatory support: experience from the REMATCH trial. J Heart Lung Transplant 2004;23:1359–65.
    Crossref | Pubmed
  61. Miller LW, Pagani FD, Russell SD, et al. Use of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med 2007;357:885–96.
    Crossref | Pubmed
  62. Holman WL, Pae WE, Teutenberg JJ, et al. INTERMACS: interval analysis of registry data. J Am Coll Surg 2009;208:755–61.
    Crossref | Pubmed
  63. Topkara VK, Kondareddy S, Malik F, et al. Infectious complications in patients with left ventricular assist device: etiology and outcomes in the continuous-flow era. Ann Thorac Surg 2010;90:1270–7.
    Crossref | Pubmed
  64. Hannan MM, Husain S, Mattner F, et al. International Society for Heart and Lung Transplantation. Working formulation for the standardization of definitions of infections in patients using ventricular assist devices. J Heart Lung Transplant 2011;30:375–84.
    Crossref | Pubmed
  65. Farrar DJ, Bourque K, Dague CP, et al. Design features, developmental status, and experimental results with the Heartmate III centrifugal left ventricular assist system with a magnetically levitated rotor. ASAIO J 2007;53:310–5.
    Crossref | Pubmed
  66. Mesa KJ, Ferreira A, Castillo S, et al.The MVAD® Pump: Motor Stator Core Loss Characterization. ASAIO J 2014 Nov 24. [Epub ahead of print]
    Crossref | Pubmed
  67. Burkhoff D, Maurer MS, Joseph SM, et al. Left Atrial Decompression Pump for Severe Heart Failure With Preserved Ejection Fraction: Theoretical and Clinical Considerations. JACC Heart Fail 2015 Mar 3 [Epub ahead of print]
    Crossref | Pubmed