Associate editor: Yiannis ChatzizisisVentricular assist devices: Pharmacological aspects of a mechanical therapy
Introduction
Heart failure (HF) is a global epidemic that despite remarkable advances in medical therapy remains a significant cause of morbidity and mortality (Roger et al., 2011). Heart transplantation, considered to be the most effective therapy for patients with end-stage HF, is limited by donor availability. Furthermore, older patients (typically > 65 years of age) are less likely to be considered appropriate candidates for heart transplantation (Mehra et al., 2006). As a result, and in conjunction with improvements in left ventricular assist device (LVAD) technology that have dramatically improved outcomes, the number of implanted LVADs has grown exponentially (Kirklin et al., 2011).
In current clinical practice, LVADs are used either to provide short-term hemodynamic support during high-risk cardiac surgery or percutaneous coronary interventions (paracorporeal and percutaneous LVADs), or to provide long-term mechanical circulatory support (implantable durable LVADs). Durable LVADs are currently used as a bridge to transplant, as permanent or destination therapy, and in selected patients as a temporizing measure until native myocardial function improvement occurs, allowing explantation of the device (bridge to recovery). Favorable results of clinical trials of the continuous-flow HeartMate II LVAD led to the approval by the Food and Drug Administration of this device for clinical use, first as a bridge to transplant in 2008 and later as destination therapy in 2010 (Miller et al., 2007, Slaughter et al., 2009). Currently, more than 98% of the durable LVADs implanted are continuous-flow devices (Kirklin et al., 2011) and we will therefore focus on continuous-flow durable LVADs in this review.
Even though LVADs are a standalone therapy, their effects on the hemodynamics of both the unsupported right ventricle and the supported left ventricle, on the vascular, hematologic and immune systems and the complications associated with their use require multiple and complex pharmacologic interventions to ensure the continued and proper function of these devices while improving patient outcomes. Herein, we review recent clinical studies, pharmacological advances and current practices in the care of LVAD supported patients.
Section snippets
Anticoagulation management
- a.
Standard anticoagulation strategies
Anticoagulation strategies in the mechanical circulatory support field have represented a considerable challenge for decades. The invaluable experience acquired from the first-in-human chronic application of the total artificial heart in Barney Clark at the University of Utah (De Vries et al., NEJM 1984), prophetically indicated both in terms of clinical outcomes and in post-mortem pathology studies, that thromboembolic complications are probably the most
Management of bleeding
- a.
Perioperative management
Bleeding is the most common perioperative complication after LVAD implantation (Haj-Yahia et al., 2007, Miller et al., 2007, Slaughter et al., 2009). Therefore, a thorough preoperative evaluation is essential for minimizing bleeding and transfusion requirements. Patients with advanced HF frequently present with multiple comorbidities, poor nutritional status, anemia, and deficiency of coagulation factors, all of which may predispose them to an increase in the risk of
Management of LVAD thrombosis
Device thrombosis is a complication of circulatory support with continuous-flow LVADs that is associated with significant morbidity and mortality, often requiring exchange of the LVAD. The incidence of LVAD thrombosis in the HeartMate II bridge to transplant and destination therapy trials was 1.5% and 3.76%, respectively (Miller et al., 2007, Slaughter et al., 2009) . Thrombosis can occur at different levels, including the inflow and outflow cannula, or in the pump itself, a scenario frequently
Right ventricular failure: prevention and management
The right and left ventricle are connected in series and interact with each other hemodynamically due to the anatomic coupling provided by the shared interventricular septum and common muscle fibers. The impact of LV support by a LVAD on the geometry of the right ventricle, hemodynamics and function can be complex. The reduction of left ventricular filling pressures by the LVAD can substantially decrease the pulmonary vascular resistance, right ventricle afterload and in that way improve right
Management of infections
LVAD infections are classified as VAD-specific infections (related to the hardware, do not occur in non-VAD patients), VAD-related infections (can also occur in non-VAD patients, e.g. infective endocarditis) and non-VAD infections (unrelated to the VAD presence, e.g. urinary tract infection) (Hannan et al., 2011). Infections represent a significant cause of morbidity and mortality in patients supported with LVADs (Monkowski et al., 2007, Kirklin et al., 2010, Kirklin et al., 2011). Percutaneous
Management of arrhythmias
- a.
Ventricular arrhythmias
Ventricular arrhythmias are common among patients with end-stage HF supported by LVADs, and their incidence during circulatory support appears to be higher in patients with ischemic heart disease (Arai et al., 1991, Oz et al., 1994, Ziv et al., 2005, Drakos et al., 2011b). Although there are reports that these potentially lethal arrhythmias can be tolerated surprisingly well by patients on LVAD support (Busch et al., 2011, Patel et al., 2011b, Sims et al., 2011), their
Management of systemic hypertension
Hypertension is highly prevalent in patients with HF with as many as 75% having antecedent hypertension (Roger et al., 2011). While hypertension may be masked in advanced stages of the disease due to reduced cardiac output/cardiac function, hypertension may resurface after LVAD placement. Results from an animal study also suggest that the renin–angiotensin system may be upregulated in the setting of circulatory support with a continuous-flow device (Ootaki et al., 2008). Central arterial-wave
HLA-allosensitization: prevention and treatment strategies
Development of antibodies to HLA is a common complication associated with the use of LVADs that deserves special consideration in patients awaiting heart transplantation. HLA-allosensitization in LVAD supported patients is thought to be caused by the continuous contact of nonbiological material with the patient's blood. In order to detect allosensitization, transplant candidates undergo testing that exposes recipient serum to HLA antigens through different techniques, with a result being
Myocardial reverse remodeling: combining mechanical and pharmacological interventions
Myocardial injury (i.e. myocardial infarction, cardiotoxic chemotherapy, etc.) can lead to a series of molecular, structural and functional changes referred to as myocardial remodeling. Ventricular volume and pressure overload are thought to be responsible for perpetuating the vicious cycle of myocardial dysfunction and worsening HF (Katz, 2002). The use of LVAD support effectively unloads the LV and could potentially disrupt the vicious cycle, thus allowing reversal of the maladaptive changes
Conclusions
We expect that the use of LVADs will continue to increase steadily in the near future, a result of the increasing prevalence of HF in the aging population and the advances in LVAD technology combined with continued limited donor availability (Stehlik et al. 2011 ISHLT Registry report) and potential changes in donor organ allocation policies (Moazami et al., 2011). Consequently, a better understanding of the different pharmacological interventions, their efficacy and safety profile in this
Acknowledgments
The authors are indebted to John N. Nanas for his enormous clinical and academic support over the years
References (120)
- et al.
Implantable cardioverter-defibrillator shocks in patients with a left ventricular assist device
J Heart Lung Transplant
(2010) - et al.
Incidence of ventricular arrhythmias in patients on long-term support with a continuous-flow assist device (HeartMate II)
J Heart Lung Transplant
(2009) - et al.
Cardiac cachexia: a syndrome with impaired survival and immune and neuroendocrine activation
Chest
(1999) - et al.
Randomized, double-blind trial of inhaled nitric oxide in LVAD recipients with pulmonary hypertension
Ann Thorac Surg
(1998) - et al.
Use of rituximab to decrease panel-reactive antibodies
J Heart Lung Transplant
(2005) - et al.
Ventricular arrhythmias during left ventricular assist device support
Am J Cardiol
(2007) - et al.
High incidence of thromboembolic events in left ventricular assist device patients treated with recombinant activated factor VII
J Heart Lung Transplant
(2009) - et al.
Asymptomatic sustained ventricular fibrillation in a patient with left ventricular assist device
Ann Emerg Med
(2011) - et al.
Anticoagulative management of patients requiring left ventricular assist device implantation and suffering from heparin-induced thrombocytopenia type II
Ann Thorac Surg
(2000) - et al.
Direct thrombolytic therapy for intraventricular thrombosis in patients with the Jarvik 2000 left ventricular assist device
J Heart Lung Transplant
(2005)
Arteriovenous malformation and gastrointestinal bleeding in patients with the HeartMate II left ventricular assist device
J Heart Lung Transplant
Use of intravenous immunoglobulin in sensitized LVAD recipients
Transplant Proc
Risk factors predictive of right ventricular failure after left ventricular assist device implantation
Am J Cardiol
Impact of mechanical unloading on microvasculature and associated central remodeling features of the failing human heart
J Am Coll Cardiol
Prior human leukocyte antigen-allosensitization and left ventricular assist device type affect degree of post-implantation human leukocyte antigen-allosensitization
J Heart Lung Transplant
Low-dose prophylactic intravenous immunoglobulin does not prevent HLA sensitization in left ventricular assist device recipients
Ann Thorac Surg
Prevalence and risks of allosensitization in HeartMate left ventricular assist device recipients: The impact of leukofiltered cellular blood product transfusions
J Thorac Cardiovasc Surg
Reverse remodeling during long-term mechanical unloading of the left ventricle
J Mol Cell Cardiol
Reverse electrophysiologic remodeling after cardiac mechanical unloading for end-stage nonischemic cardiomyopathy
Ann Thorac Surg
Concomitant left ventricular assist device placement and cryoablation for treatment of ventricular tachyarrhythmias associated with heart failure
Ann Thorac Surg
Long-term follow-up of Thoratec ventricular assist device bridge-to-recovery patients successfully removed from support after recovery of ventricular function
J Heart Lung Transplant
Dental treatment of a patient with an implanted left ventricular assist device: Expanding the frontiers
Oral Surg Oral Med Oral Pathol Oral Radiol Endod
Risk score derived from pre-operative data analysis predicts the need for biventricular mechanical circulatory support
J Heart Lung Transplant
Midterm experience with the Jarvik 2000 axial flow left ventricular assist device
J Thorac Cardiovasc Surg
Working formulation for the standardization of definitions of infections in patients using ventricular assist devices
J Heart Lung Transplant
Nutrition assessment and management of left ventricular assist device patients
J Heart Lung Transplant
Infection in permanent circulatory support: Experience from the REMATCH trial
J Heart Lung Transplant
Increased expression of stem cell factor and its receptor after left ventricular assist device support: A potential novel target for therapeutic interventions in heart failure
J Heart Lung Transplant
Impact of left ventricular assist device (LVAD)-mediated humoral sensitization on post-transplant outcomes
J Heart Lung Transplant
Vitamin K reduces bleeding in left ventricular assist device recipients
J Heart Lung Transplant
Cardiovascular mortality among heart transplant recipients with asymptomatic antibody-mediated or stable mixed cellular and antibody-mediated rejection
J Heart Lung Transplant
A clinical correlation study of severity of antibody-mediated rejection and cardiovascular mortality in heart transplantation
J Heart Lung Transplant
Second INTERMACS annual report: more than 1,000 primary left ventricular assist device implants
J Heart Lung Transplant
Third INTERMACS Annual Report: The evolution of destination therapy in the United States
J Heart Lung Transplant
Effect of sildenafil on pulmonary artery pressure, systemic pressure, and nitric oxide utilization in patients with left ventricular assist devices
Ann Thorac Surg
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
Impact of heparin-induced thrombocytopenia on outcome in patients with ventricular assist device support: Single-institution experience in 358 consecutive patients
Ann Thorac Surg
Acute impact of left ventricular unloading by left ventricular assist device on the right ventricle geometry and function: Effect of nitric oxide inhalation
J Thorac Cardiovasc Surg
Gastrointestinal bleeding from arteriovenous malformations in patients supported by the Jarvik 2000 axial-flow left ventricular assist device
J Heart Lung Transplant
Transplantation of high panel-reactive antibody left ventricular assist device patients without crossmatch using on-bypass pheresis and alemtuzumab
Ann Thorac Surg
Factors influencing HLA sensitization in implantable LVAD recipients
Ann Thorac Surg
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
Treatment of infected left ventricular assist device using antibiotic-impregnated beads
Ann Thorac Surg
Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates—2006
J Heart Lung Transplant
HeartMate II implantation in patients with heparin-induced thrombocytopenia type II
Ann Thorac Surg
Stable patients on left ventricular assist device support have a disproportionate advantage: Time to re-evaluate the current UNOS policy
J Heart Lung Transplant
PDE3 inhibition in dilated cardiomyopathy
Curr Opin Pharmacol
Reduced pulsatility induces periarteritis in kidney: Role of the local renin–angiotensin system
J Thorac Cardiovasc Surg
Malignant ventricular arrhythmias are well tolerated in patients receiving long-term left ventricular assist devices
J Am Coll Cardiol
Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans. Histological analysis of cell survival and differentiation
J Am Coll Cardiol
Cited by (14)
Arrhythmias after left ventricular assist device implantation: Incidence and management
2018, Trends in Cardiovascular MedicineCitation Excerpt :Digoxin slows ventricular response to AF through enhancement of parasympathetic tone, and while generally ineffective as sole therapy, may be a useful adjunct to β-blocker therapy [17,18]. Calcium channel blockers are another class of drugs that may be used to achieve rate control in LVAD recipients, though are not generally used in patients with systolic heart failure [19]. Rate control may also be achieved non-pharmacologically via ablation of the AV node, though this does necessitate ventricular pacing following ablation.
Team-based Care for Advanced Heart Failure
2015, Heart Failure ClinicsCitation Excerpt :LVAD-related infections represent a significant cause of morbidity and mortality in patients supported with LVADs. Multidisciplinary approaches directed at preventing and treating infectious complications during LVAD support have been previously described,36 which in the authors' experience has resulted in improved outcomes. As the number of patients on LVAD support continues to grow, multidisciplinary teams are now facing an increasing number of non-LVAD-related adverse events.
Minimally invasive apical cannulation and cannula design for short-term mechanical circulatory support devices
2022, BMC Cardiovascular DisordersPostoperative Management Strategies in Mechanical Circulatory Support Patients
2020, Mechanical Support for Heart Failure: Current Solutions and New TechnologiesCurrent and emerging pharmacotherapy for the treatment of infections following open-heart surgery
2019, Expert Opinion on PharmacotherapyProgress in gene therapy for chronic heart failure
2018, Heart Surgery Forum