Garrick C. Stewart

Mechanical Circulatory Support for Advanced Heart Failure Patients and Technology in Evolution

After nearly 50 years of clinical development, durable mechanical circulatory support (MCS) devices are widely available for patients with advanced heart failure. The field of circulatory support has matured dramatically in recent years, thanks to the advent of smaller, rotary pumps. The resulting transition away from older pulsatile devices has been swift. Accelerated use of continuous-flow left ventricular assist devices (LVADs) for long-term support has changed the face of advanced heart failure care. MCS candidate selection, risk stratification, and management strategies are evolving in tandem with new pump technology, producing a shift in the profiles of patients being considered for MCS. Timely referral for MCS evaluation and appropriate implantation now depends on familiarity with recent advances in pump design and clinical outcomes. This review, the first in a series on Advances in Mechanical Circulatory Support , will focus on durable intracorporeal LVADs used in adults with advanced heart failure, and highlight the evolution in both patients and technology. The modern era of cardiac surgery began in 1953 with the first clinical use of cardiopulmonary bypass, allowing increasingly complex operations and laying the foundation for circulatory assist devices.1 Shortly after its invention, the heart-lung machine began to be used to support patients with postcardiotomy cardiogenic shock to facilitate recovery after failed operations. By the 1960s, simple cardiac assist devices began to replace cardiopulmonary bypass for the treatment of postcardiotomy shock (Figure 1). The first clinical use of an implantable artificial ventricle was reported by Liotta et al2 in 1963. This primitive ventricular assist device (VAD) consisted of a pneumatically driven, tubular displacement pump with a valved conduit connecting the left atrium to the descending thoracic aorta. The pump provided partial left ventricular bypass for 4 days after postoperative cardiac arrest before the patient died of multiorgan failure. Inspired by …

The vexing problem of thrombosis in long-term mechanical circulatory support

Durable left ventricular assist devices (LVADs) have not only enhanced longevity but also conferred sustained improvements in quality of life, symptom control, and functional capacity in patients with medically refractory advanced heart failure. Problems with device-related infection, bleeding, neurologic events, right-sided heart failure, and device malfunction have dominated the clinical care of patients living on mechanical support. Even as adoption of durable LVADs accelerated globally, we began to encounter a growing dilemma of pump malfunction caused by thrombosis. In early 2011, clinicians began to notice a spike in the incidence of pump thrombosis with the HeartMate II (Thoratec Corp, Pleasanton, CA) LVAD. By 2012, the problem of thrombosis in LVADs began to consume most of the scientific direction as centers and collaborative groups began to dissect this nascent phenomenon. In this perspective, we describe the magnitude and implications of pump thrombosis, discuss secular and management trends in this unique population, attempt to dissect the problem at its root, offer guidance on surveillance and therapeutic principles, and outline issues that deserve our immediate and collaborative attention.

Patient Expectations From Implantable Defibrillators to Prevent Death in Heart Failure

BACKGROUND Indications for implantable cardioverter-defibrillators (ICDs) in heart failure (HF) are expanding and may include more than 1 million patients. This study examined patient expectations from ICDs for primary prevention of sudden death in HF. METHODS AND RESULTS Study participants (n = 105) had an EF <35% and symptomatic HF, without history of ventricular tachycardia/fibrillation or syncope. Subjects completed a written survey about perceived ICD benefits, survival expectations, and circumstances under which they might deactivate defibrillation. Mean age was 58, LVEF 21%, 40% were New York Heart Association Class III-IV, and 65% already had a primary prevention ICD. Most patients anticipated more than10 years survival despite symptomatic HF. Nearly 54% expected an ICD to save >or=50 lives per 100 during 5 years. ICD recipients expressed more confidence that the device would save their own lives compared with those without an ICD (P < .001). Despite understanding the ease of deactivation, 70% of ICD recipients indicated they would keep the ICD on even if dying of cancer, 55% even if having daily shocks, and none would inactivate defibrillation even if suffering constant dyspnea at rest. CONCLUSIONS HF patients anticipate long survival, overestimate survival benefits conferred by ICDs, and express reluctance to deactivate their devices even for end-stage disease.

Evaluation for a Ventricular Assist Device: Selecting the Appropriate Candidate

Case presentation: A 57-year-old woman with ischemic and valvular heart disease presents with progressive heart failure while awaiting cardiac transplantation. Several years ago, after a large anterior myocardial infarction, she underwent 4-vessel CABG. Her subsequent course was complicated by atrial fibrillation and then recurrent heart failure. She also developed progressive aortic stenosis and mitral and tricuspid regurgitation and underwent aortic valve replacement with a 17-mm St. Jude valve, as well as mitral and tricuspid valvuloplasty. Two years later, she developed worsening symptoms of heart failure. She continued to fail despite escalating medical therapy and was listed for cardiac transplantation 6 months before this hospitalization. She is now admitted with severe heart failure and has been stabilized on intravenous positive inotropic therapy. She is 5 feet 2 inches tall, weighs 104 pounds, and has a body surface area of 1.4 m2. What are the best options to manage her as she awaits transplantation: Continued parenteral inotropic support, a ventricular assist device (VAD), or both as a bridge to transplantation? Heart failure is the final pathway of a progressive disease that can originate from a variety of cardiovascular processes. Improved acute medical care and prevention of sudden cardiac death have led to an increased prevalence of advanced heart failure. The prognosis of heart failure is dismal, with 50% of patients dead within 4 years, a percentage that matches that of many common malignancies.1 Of those hospitalized with an acute exacerbation, the mortality rate within 1 year has been reported to be between 30% and 50%.2,3 Numerous factors in clinical studies consistently have been identified to be associated with poor prognosis: Advanced age, decreased blood pressure, reduced ejection fraction, chronic kidney disease, diabetes mellitus, anemia, hyponatremia, and persistently high levels of natriuretic peptides. Yet, no single clinical variable or …

Keeping left ventricular assist device acceleration on track.

Almost 50 years ago, the National Heart, Lung, and Blood Institute launched the journey of mechanical circulatory support. These pioneers have included innovative engineers, cardiac surgeons, and stalwart patients accompanied by devoted families, who together have led us to a horizon where widespread clinical utilization is finally within sight. The pace of progress is always slower than projected. Despite our impatience, we should not rush too far beyond the light of the wagons onto terrain that is less hospitable to medical technological advances than it was 50 years ago. Since the approval of a continuous-flow destination device in January 2010, there has already been a 10-fold increase in the implantation of left ventricular assist devices (LVADs) for lifetime support, the major avenue for expansion of circulatory support. We would join advocates for more systematic evaluation of lifetime ventricular assist device (VAD) therapy in the patients listed with high priority for transplantation (a small population) and ambulatory patients with class IV symptoms (a population of unknown size and comorbidities). It is our position, however, that the current basis of evidence for selection and management of patients with LVAD does not support more aggressive acceleration of LVAD utilization than is already underway. After decades of painstaking incremental development, recent clinical progress has been rapid, with each device hailed as the breakthrough until overtaken by the next. The pulsatile Novacor (WorldHeart, Inc., Salt Lake City, UT) and Heartmate (Thoratec, Inc., Pleasanton, CA) devices were approved to keep people alive as a bridge to transplant without randomized comparison to medical therapy. The first and only randomized, controlled trial of an implantable circulatory support device compared with medical therapy was instead for lifetime support without transplantation; the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial with the pulsatile Heartmate …

Implant Strategies Change Over Time and Impact Outcomes : Insights From the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support)

OBJECTIVES This study investigated how the initial intended strategy at left ventricular assist device (LVAD) implantation influenced patient outcomes. BACKGROUND Left ventricular assist device implantation strategy impacts candidate selection, reimbursement, and clinical trial design; however, concepts of device strategy are continuing to evolve. METHODS For patients entered in the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) receiving a primary continuous flow LVAD between March 2006 and March 2011, initial strategies were bridge to transplant (BTT), bridge to candidacy (BTC) for transplant, and destination therapy (DT). Primary analyses compared BTT, BTC, and DT outcomes at 6, 12, and 24 months. RESULTS Among 2,816 primary LVAD recipients, implant strategy was 1,060 (38%) BTT, 1,162 (42%) BTC (likely to be listed 796, moderately likely 282, unlikely 84), and 553 (20%) DT. Compared with BTC/DT, those listed at implant (BTT) had similar degrees of ventricular dysfunction and hemodynamic derangement but generally less comorbidity. Survival (alive with LVAD or transplanted) was superior at 24 months for BTT versus BTC versus DT (77.7% vs.70.1% vs. 60.7%, respectively, p < 0.0001). Strategic intent changed over time, at 2 years 43.5% of BTT patients were no longer listed for transplant, but 29.3% of BTC patients were listed for transplant. CONCLUSIONS The currently accepted indications only account for 58% of LVAD implants. Across indications, patients differ by the number and types of comorbidities rather than the need for hemodynamic support. Regardless of initial implant strategy, patients often have long durations of support, and strategies often change over time, challenging the regulatory categorization of LVAD recipients as either BTT or DT.

Thresholds of Physical Activity and Life Expectancy for Patients Considering Destination Ventricular Assist Devices

BACKGROUND Current implantable left ventricular assist devices (LVAD) improve survival and function for patients with very late stage heart failure (HF) but may also offer benefit before inotrope dependence. Debate continues about selection of HF patients for LVAD therapy. We sought to determine what level of personal risk and disability HF patients thought would warrant LVAD therapy. METHODS The study included 105 patients with symptomatic HF and an LV ejection fraction (EF) < 35% who were given a written paragraph about LVADs and asked about circumstances under which they would consider such a device. New York Heart Association (NYHA) functional class, time trade-off utility, and patient-assessed functional score were determined. RESULTS Participants (mean age, 58 years) had an LVEF of 21%. The median duration of HF was 5 years, and 65% had a primary prevention implantable cardioverter defibrillator. Presented with a scenario of bed-ridden HF, 81% stated they would definitely or probably want an LVAD; 50% would consider LVAD to prolong survival if HF survival were predicted to be < 1 year and 75% if < 6 months. Meanwhile, 44% would consider LVAD if they could only walk < 1 block and 64% if they could not dress without stopping. Anticipated thresholds did not differ by NYHA class, time trade-off, or functional score. CONCLUSIONS Patient thresholds for LVAD insertion parallel objective survival and functional data. HF patients would be receptive to referral for discussion of LVAD by the time expected mortality is within 6 to 12 months and activity remains limited to less than 1 block.

Myocardial Parvovirus B19 Persistence: Lack of Association with Clinicopathologic Phenotype in Adults with Heart Failure

Background—Multiple viruses have been isolated from the heart, but their significance remains controversial. We sought to determine the prevalence of cardiotropic viruses in endomyocardial biopsy (EMB) samples from adult patients with heart failure (HF) and to define the clinicopathologic profile of patients exhibiting viral positivity. Methods and Results—EMB from 100 patients (median ejection fraction, 30%; interquartile range [IQR], 20% to 45%) presenting for cardiomyopathy evaluation (median symptom duration, 5 months; IQR, 1 to 13 months) were analyzed by polymerase chain reaction for adenovirus, cytomegalovirus, enteroviruses, Epstein-Barr virus, and parvovirus B19. Each isolate was sequenced, and viral load was determined. Parvovirus B19 was the only virus detected in EMB samples (12% of subjects). No patient had antiparvovirus IgM antibodies, but all had IgG antibodies, suggesting viral persistence. The clinical presentation of parvovirus-positive patients was markedly heterogeneous with both acute and chronic HF, variable ventricular function, and ischemic cardiomyopathy. No patient met Dallas histopathologic criteria for active or borderline myocarditis. Two patients with a positive cardiac MRI and presumed “parvomyocarditis” had similar viral loads to autopsy controls without heart disease. The oldest parvovirus-positive patients were positive for genotype 2, suggesting lifelong persistence in the myocardium. Conclusions—Parvovirus B19 was the only virus isolated from EMB samples in this series of adult patients with HF from the United States. Positivity was associated with a wide array of clinical presentations and HF phenotypes. Our studies do not support a causative role for parvovirus B19 persistence in HF and, therefore, advocate against the use of antiviral therapy for these patients.Background— Multiple viruses have been isolated from the heart, but their significance remains controversial. We sought to determine the prevalence of cardiotropic viruses in endomyocardial biopsy (EMB) samples from adult patients with heart failure (HF) and to define the clinicopathologic profile of patients exhibiting viral positivity. Methods and Results— EMB from 100 patients (median ejection fraction, 30%; interquartile range [IQR], 20% to 45%) presenting for cardiomyopathy evaluation (median symptom duration, 5 months; IQR, 1 to 13 months) were analyzed by polymerase chain reaction for adenovirus, cytomegalovirus, enteroviruses, Epstein-Barr virus, and parvovirus B19. Each isolate was sequenced, and viral load was determined. Parvovirus B19 was the only virus detected in EMB samples (12% of subjects). No patient had antiparvovirus IgM antibodies, but all had IgG antibodies, suggesting viral persistence. The clinical presentation of parvovirus-positive patients was markedly heterogeneous with both acute and chronic HF, variable ventricular function, and ischemic cardiomyopathy. No patient met Dallas histopathologic criteria for active or borderline myocarditis. Two patients with a positive cardiac MRI and presumed “parvomyocarditis” had similar viral loads to autopsy controls without heart disease. The oldest parvovirus-positive patients were positive for genotype 2, suggesting lifelong persistence in the myocardium. Conclusions— Parvovirus B19 was the only virus isolated from EMB samples in this series of adult patients with HF from the United States. Positivity was associated with a wide array of clinical presentations and HF phenotypes. Our studies do not support a causative role for parvovirus B19 persistence in HF and, therefore, advocate against the use of antiviral therapy for these patients.

Myocardial Infarction Triggers Chronic Cardiac Autoimmunity in Type 1 Diabetes

Acute myocardial infarction triggers an autoimmune attack on the heart in a mouse model of type 1 diabetes and in human type 1 diabetic patients. After a Heart Attack, Diabetics Skip a Beat There’s no way to sugarcoat it: Patients with type 1 (autoimmune) diabetes experience more severe downstream symptoms after a myocardial infarction (MI)—heart attack—than do nondiabetic individuals. MI triggers an inflammatory response, which promotes cardiac repair in healthy patients but has unclear effects in those with preexisting autoimmunity. Gottumukkala et al. now show that the increased morbidity and mortality of type 1 diabetics after MI may be caused by the immune system attacking the damaged heart. In a humanized mouse model of diabetes, the authors found that MI gives rise to post-infarction autoimmune (PIA) syndrome, which is characterized by lymphocytic infiltration and both cardiac autoantibody and autoimmune T cell responses, which are intriguingly restricted to cardiac myosin. Gottumukkala et al. then detected cardiac tissue–directed autoantibodies after MI in 83% of human type 1 diabetic patients tested, but these autoantibodies were absent from type 2 diabetic patients who had suffered MI. These data suggest that an autoimmune disease such as type 1 diabetes may predispose individuals to further autoimmunity (PIA) in the context of inflammation and tissue damage. The antigen-restricted autoimmune response suggests that antigen-specific tolerance induction may be used to improve the health of diabetics after MI. Patients with type 1 diabetes (T1D) suffer excessive morbidity and mortality after myocardial infarction (MI) that is not fully explained by the metabolic effects of diabetes. Acute MI is known to trigger a profound innate inflammatory response with influx of mononuclear cells and production of proinflammatory cytokines that are crucial for cardiac repair. We hypothesized that these same pathways might exert “adjuvant effects” and induce pathological responses in autoimmune-prone T1D hosts. Here, we show that experimental MI in nonobese diabetic mice, but not in control C57BL/6 mice, results in a severe post-infarction autoimmune (PIA) syndrome characterized by destructive lymphocytic infiltrates in the myocardium, infarct expansion, sustained cardiac autoantibody production, and T helper type 1 effector cell responses against cardiac (α-)myosin. PIA was prevented by inducing tolerance to α-myosin, demonstrating that immune responses to cardiac myosin are essential for this disease process. Extending these findings to humans, we developed a panel of immunoassays for cardiac autoantibody detection and found autoantibody positivity in 83% post-MI T1D patients. We further identified shared cardiac myosin autoantibody signatures between post-MI T1D patients and nondiabetic patients with myocarditis, which were absent in post-MI type 2 diabetic patients, and confirmed the presence of myocarditis in T1D by cardiac magnetic resonance imaging techniques. These data provide experimental and clinical evidence for a distinct post-MI autoimmune syndrome in T1D. Our findings suggest that PIA may contribute to worsened post-MI outcomes in T1D and highlight a role for antigen-specific immunointervention to selectively block this pathway.

Impact of Baseline Heart Failure Burden on Post-Implantable Cardioverter-Defibrillator Mortality Among Medicare Beneficiaries

OBJECTIVES This study sought to assess the impact of baseline heart failure (HF) burden on survival with primary implantable cardioverter-defibrillator (ICD) among Medicare recipients. BACKGROUND Survival after primary ICD implantation may differ between trial and Medicare populations. METHODS Linking data from the CMS (Centers for Medicare and Medicaid Services) ICD registry and the Medicare files (2005 to 2009), we identified primary ICD recipients age ≥66 years with ejection fraction ≤35%. Number of previous HF hospitalizations (prev-HF-hosp) and length of hospitalization prior to implantation were used to define HF burden. Crude all-cause mortality was estimated. Adjusted hazard ratios (HR) were derived from Cox models. RESULTS Of 66,974 ICD recipients (73% men, 88% white, mean age 75 years), 11,876 died (average follow-up = 1.4 years), with 3-year mortality of 31%. Among patients with no prev-HF-hosp, 3-year mortality was 27% compared with 63% in those with ≥3 prev-HF-hosp (adjusted HR: 1.8). Among patients with same-day implantation, 3-year mortality was 25% compared with 53% in those with >1-week hospitalization days prior to implantation (adjusted HR: 1.9). Mortality at 3-year follow-up among the 31,685 ICD recipients with no prev-HF-hosp and same-day implantation (low HF burden) was similar to that in trials (22%). CONCLUSIONS Nearly one-third of Medicare ICD recipients died within 3 years, reflecting a population with more advanced age and disease than seen in trial populations for primary prevention ICD. Nearly one-half of Medicare recipients had a low HF burden and had a survival similar to trial ICD recipients. Future research is warranted to understand the effectiveness of primary ICD implantation among Medicare beneficiaries with heavy HF burdens.