Michael S. Kiernan

Recommendations for the Use of Mechanical Circulatory Support: Device Strategies and Patient Selection A Scientific Statement From the American Heart Association

The era of mechanical circulatory support (MCS) began in 1953 with the development of cardiopulmonary bypass to facilitate open heart surgery.1 In 1964, the National Heart Institute (now the National Heart, Lung, and Blood Institute) funded the Artificial Heart Program and became actively involved in MCS development. This led to requests for Proposals issued in 1977 and 1980, which laid the foundation for the development of implantable MCS for long-term use, including devices capable of hospital discharge, in the 1990s. Although heart transplantation is now commonplace at many hospitals, the inadequate supply of donor hearts and patient contraindications to transplantation continue to severely restrict its application. As the demand for long-term replacement of diseased hearts increases, there is a clear need for innovative, safe, and durable MCS to treat the growing population of patients with advanced heart failure (HF). Many exciting changes in the field of MCS have occurred in the past few years, including the development of smaller portable pumps and the concept of destination therapy (DT), or permanent pump placement as an alternative to heart transplantation. Currently, there are no published guidelines for the use of MCS. Thus, it is our intent that this statement will provide the contemporary cardiologist and other HF providers with an understanding of general considerations when determining the appropriateness of MCS. There is little hope that complete consensus will ever be reached on the definition of advanced HF, but most physicians caring for such patients on a regular basis readily identify the characteristics of these patients. Advanced HF patients are those with clinically significant circulatory compromise who require special care, including consideration for heart transplantation, continuous intravenous inotropic therapy, MCS, or hospice.2,3 Typically, such patients have symptoms at rest or with minimal exertion and cannot perform many activities of …

Effects of Liraglutide on Clinical Stability Among Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial

IMPORTANCE Abnormal cardiac metabolism contributes to the pathophysiology of advanced heart failure with reduced left ventricular ejection fraction (LVEF). Glucagon-like peptide 1 (GLP-1) agonists have shown cardioprotective effects in early clinical studies of patients with advanced heart failure, irrespective of type 2 diabetes status. OBJECTIVE To test whether therapy with a GLP-1 agonist improves clinical stability following hospitalization for acute heart failure. DESIGN, SETTING, AND PARTICIPANTS Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with established heart failure and reduced LVEF who were recently hospitalized. Patients were enrolled between August 2013 and March 2015 at 24 US sites. INTERVENTIONS The GLP-1 agonist liraglutide (n = 154) or placebo (n = 146) via a daily subcutaneous injection; study drug was advanced to a dosage of 1.8 mg/d during the first 30 days as tolerated and continued for 180 days. MAIN OUTCOMES AND MEASURES The primary end point was a global rank score in which all patients, regardless of treatment assignment, were ranked across 3 hierarchical tiers: time to death, time to rehospitalization for heart failure, and time-averaged proportional change in N-terminal pro-B-type natriuretic peptide level from baseline to 180 days. Higher values indicate better health (stability). Exploratory secondary outcomes included primary end point components, cardiac structure and function, 6-minute walk distance, quality of life, and combined events. RESULTS Among the 300 patients who were randomized (median age, 61 years [interquartile range {IQR}, 52-68 years]; 64 [21%] women; 178 [59%] with type 2 diabetes; median LVEF of 25% [IQR, 19%-33%]; median N-terminal pro-B-type natriuretic peptide level of 2049 pg/mL [IQR, 1054-4235 pg/mL]), 271 completed the study. Compared with placebo, liraglutide had no significant effect on the primary end point (mean rank of 146 for the liraglutide group vs 156 for the placebo group, P = .31). There were no significant between-group differences in the number of deaths (19 [12%] in the liraglutide group vs 16 [11%] in the placebo group; hazard ratio, 1.10 [95% CI, 0.57-2.14]; P = .78) or rehospitalizations for heart failure (63 [41%] vs 50 [34%], respectively; hazard ratio, 1.30 [95% CI, 0.89-1.88]; P = .17) or for the exploratory secondary end points. Prespecified subgroup analyses in patients with diabetes did not reveal any significant between-group differences. The number of investigator-reported hyperglycemic events was 16 (10%) in the liraglutide group vs 27 (18%) in the placebo group and hypoglycemic events were infrequent (2 [1%] vs 4 [3%], respectively). CONCLUSIONS AND RELEVANCE Among patients recently hospitalized with heart failure and reduced LVEF, the use of liraglutide did not lead to greater posthospitalization clinical stability. These findings do not support the use of liraglutide in this clinical situation. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01800968.

Cardiovascular Function and Treatment in β-Thalassemia Major A Consensus Statement From the American Heart Association

This aim of this statement is to report an expert consensus on the diagnosis and treatment of cardiac dysfunction in β-thalassemia major (TM). This consensus statement does not cover other hemoglobinopathies, including thalassemia intermedia and sickle cell anemia, in which a different spectrum of cardiovascular complications is typical. There are considerable uncertainties in this field, with a few randomized controlled trials relating to treatment of chronic myocardial siderosis but none relating to treatment of acute heart failure. The principles of diagnosis and treatment of cardiac iron loading in TM are directly relevant to other iron-overload conditions, including in particular Diamond-Blackfan anemia, sideroblastic anemia, and hereditary hemochromatosis. Heart failure is the most common cause of death in TM and primarily results from cardiac iron accumulation. The diagnosis of ventricular dysfunction in TM patients differs from that in nonanemic patients because of the cardiovascular adaptation to chronic anemia in non-cardiac-loaded TM patients, which includes resting tachycardia, low blood pressure, enlarged end-diastolic volume, high ejection fraction, and high cardiac output. Chronic anemia also leads to background symptomatology such as dyspnea, which can mask the clinical diagnosis of cardiac dysfunction. Central to early identification of cardiac iron overload in TM is the estimation of cardiac iron by cardiac T2* magnetic resonance. Cardiac T2* <10 ms is the most important predictor of development of heart failure. Serum ferritin and liver iron concentration are not adequate surrogates for cardiac iron measurement. Assessment of cardiac function by noninvasive techniques can also be valuable clinically, but serial measurements to establish trends are usually required because interpretation of single absolute values is complicated by the abnormal cardiovascular hemodynamics in TM and measurement imprecision. Acute decompensated heart failure is a medical emergency and requires urgent consultation with a center with expertise in its management. The first principle of management of acute heart failure is control of cardiac toxicity related to free iron by urgent commencement of a continuous, uninterrupted infusion of high-dose intravenous deferoxamine, augmented by oral deferiprone. Considerable care is required to not exacerbate cardiovascular problems from overuse of diuretics or inotropes because of the unusual loading conditions in TM. The current knowledge on the efficacy of removal of cardiac iron by the 3 commercially available iron chelators is summarized for cardiac iron overload without overt cardiac dysfunction. Evidence from well-conducted randomized controlled trials shows superior efficacy of deferiprone versus deferoxamine, the superiority of combined deferiprone with deferoxamine versus deferoxamine alone, and the equivalence of deferasirox versus deferoxamine.

Role of Biomarkers for the Prevention, Assessment, and Management of Heart Failure A Scientific Statement From the American Heart Association

Background and Purpose: Natriuretic peptides have led the way as a diagnostic and prognostic tool for the diagnosis and management of heart failure (HF). More recent evidence suggests that natriuretic peptides along with the next generation of biomarkers may provide added value to medical management, which could potentially lower risk of mortality and readmissions. The purpose of this scientific statement is to summarize the existing literature and to provide guidance for the utility of currently available biomarkers. Methods: The writing group used systematic literature reviews, published translational and clinical studies, clinical practice guidelines, and expert opinion/statements to summarize existing evidence and to identify areas of inadequacy requiring future research. The panel reviewed the most relevant adult medical literature excluding routine laboratory tests using MEDLINE, EMBASE, and Web of Science through December 2016. The document is organized and classified according to the American Heart Association to provide specific suggestions, considerations, or contemporary clinical practice recommendations. Results: A number of biomarkers associated with HF are well recognized, and measuring their concentrations in circulation can be a convenient and noninvasive approach to provide important information about disease severity and helps in the detection, diagnosis, prognosis, and management of HF. These include natriuretic peptides, soluble suppressor of tumorgenicity 2, highly sensitive troponin, galectin-3, midregional proadrenomedullin, cystatin-C, interleukin-6, procalcitonin, and others. There is a need to further evaluate existing and novel markers for guiding therapy and to summarize their data in a standardized format to improve communication among researchers and practitioners. Conclusions: HF is a complex syndrome involving diverse pathways and pathological processes that can manifest in circulation as biomarkers. A number of such biomarkers are now clinically available, and monitoring their concentrations in blood not only can provide the clinician information about the diagnosis and severity of HF but also can improve prognostication and treatment strategies.

Antibody-Mediated Rejection in Cardiac Transplantation: Emerging Knowledge in Diagnosis and Management A Scientific Statement From the American Heart Association

Antibody-mediated rejection (AMR) of the cardiac allograft is a poorly defined and challenging diagnosis for transplant recipients and their clinicians. Although even its very existence in heart transplantation was debated until relatively recently, improved immunopathologic and serological techniques to detect myocardial capillary complement deposition and circulating anti-HLA (human leukocyte antigen) antibodies have led to the detection of a spectrum of newly uncovered immunologic changes that characterize AMR. The earliest standardized clinical and pathological criteria for the diagnosis of AMR in heart transplantation became available in 2004, the result of a task force assembled by the International Society for Heart and Lung Transplantation (ISHLT). In 2006, the criteria were refined by the ISHLT Immunopathology Task Force (Table 1). These revisions provide 4 categories of diagnostic criteria: clinical, histopathologic, immunopathologic, and serological assessment.1 Despite these published criteria, currently >50% of heart transplant centers make the diagnosis of AMR based on cardiac dysfunction and the lack of cellular infiltrates on the heart biopsy (preconference survey included in the ISHLT consensus article).2 More recently, the ISHLT Consensus Conference on AMR has redefined the pathological diagnosis of AMR.3 The 2013 ISHLT “Working Formulation for the Standardization of Nomenclature in the Pathologic Diagnosis of Antibody-Mediated Rejection in Heart Transplantation” was published in December 2013. This document provided an update to the 2010 consensus conference.4 It is anticipated that this update to the definition of AMR will reduce variations in the diagnosis of AMR, providing a platform for the development of standardized therapies. The goal of the present scientific statement is to provide the heart transplant professional with an overview of the current status of the diagnosis and treatment of AMR in the cardiac allograft based on recent consensus conferences and the published literature. We include recommendations to facilitate evolving standardization and strategies …

Effects of a percutaneous mechanical circulatory support device for medically refractory right ventricular failure

BACKGROUND Medically refractory right ventricular failure (MR-RVF) is associated with high in-hospital mortality and is managed with surgical assist devices, atrial septostomy, or extracorporeal membrane oxygenation. This study explored the hemodynamic effect associated with a percutaneous RV support device (pRVSD) for MR-RVF. METHODS Between 2008 and 2010, 9 patients with MR-RVF, defined as cardiogenic shock despite maximal medical therapy, were treated with a pRVSD. Medical records were reviewed for demographics, hemodynamic and laboratory data, and details of pRVSD implantation. RESULTS MR-RVF was due to severe sepsis in 1 patient (11.1%), post-cardiotomy syndrome in 2 (22.2%), and acute inferior wall myocardial infarction (IWMI) in 6 (66.7%). Five patients underwent right internal jugular-to-femoral cannulation, and 4 required bifemoral cannulation. No intra-procedural deaths or major vascular complications requiring surgical or peripheral intervention occurred. Time from admission to pRVSD implantation was 2.9 ± 3.3 days, with an average of 6516 ± 698 rotations/min, providing flow at 3.3 ± 0.4 liters/min. Mean duration of pRVSD activation was 3.1 ± 1.8 days. Compared with pre-procedural values, mean arterial pressure (57 ± 7 vs 75 ± 19 mm Hg, p < 0.05), right atrial pressure (22 ± 3 vs 15 ± 6 mm Hg, p < 0.05), cardiac index (1.5 ± 0.4 vs 2.3 ± 0.5 liters/min/m(2), p < 0.05), mixed venous oxygen saturation (40 ± 14 vs 58 ± 4 percent, p < 0.05), and RV stroke work (3.4 ± 3.9 vs 9.7 ± 6.8 g · m/beat, p < 0.05) improved significantly within 24 hours of pRVSD implantation. In-hospital mortality was 44% (n = 4). Time from admission to pRVSD placement was lower in patients who survived to hospital discharge (0.9 ± 0.8 days) vs non-survivors (4.8 ± 3.5 days; p = 0.04). All survivors presented with IWMI. CONCLUSION Use of a pRVSD for MR-RVF is feasible and associated with improved hemodynamics. Algorithms promoting earlier pRVSD use in MR-RVF warrant further investigation.

Improved Survival after Heart Failure: A Community-based Perspective

Background Heart failure is a highly prevalent, morbid, and costly disease with a poor long‐term prognosis. Evidence‐based therapies utilized over the past 2 decades hold the promise of improved outcomes, yet few contemporary studies have examined survival trends in patients with acute heart failure. The primary objective of this population‐based study was to describe trends in short‐ and long‐term survival in patients hospitalized with acute decompensated heart failure (ADHF). A secondary objective was to examine patient characteristics associated with decreased long‐term survival. Methods and Results We reviewed the medical records of 9748 patients hospitalized with ADHF at all 11 medical centers in central Massachusetts during 1995, 2000, 2002, and 2004. Patients hospitalized with ADHF were more likely to be elderly and to have been diagnosed with multiple comorbidities in 2004 compared with 1995. Over this period, survival was significantly improved in‐hospital, and at 1, 2, and 5 years postdischarge. Five‐year survival rates increased from 20% in 1995 to 29% in 2004. Although survival improved substantially over time, older patients and patients with chronic kidney disease, chronic obstructive pulmonary disease, anemia, low body mass index, and low blood pressures had consistently lower postdischarge survival rates than patients without these comorbidities. Conclusion Between 1995 and 2004, patients hospitalized with ADHF have become older and increasingly comorbid. Although there has been a significant improvement in survival among these patients, their long‐term prognosis remains poor, as fewer than 1 in 3 patients hospitalized with ADHF in 2004 survived more than 5 years.

Pulmonary Artery Pulsatility Index Is Associated With Right Ventricular Failure After Left Ventricular Assist Device Surgery

BACKGROUND Right ventricular failure (RVF) is a major cause of morbidity and mortality after CF-LVAD implantation. We explored the association of pulmonary artery compliance (PAC), pulmonary artery elastance (PAE), and pulmonary artery pulsatility index (PAPi) in addition to established parameters as preoperative determinants of postoperative RVF after CF-LVAD surgery. METHODS AND RESULTS We retrospectively reviewed 132 consecutive CF-LVAD implantations at Tufts Medical Center from 2008 to 2013. Clinical, hemodynamic, and echocardiographic data were studied. RVF was defined as the unplanned need for a right ventricular assist device or inotrope dependence for ≥14 days. Univariate analysis was performed. RVF occurred in 32 of 132 patients (24%). PAC and PAE were not changed, whereas the PAPi was lower among patients with versus without postoperative RVF (1.32 ± 0.46 vs 2.77 ± 1.16; P < .001). RA pressure, RA to pulmonary capillary wedge pressure ratio (RA:PCWP), and RV stroke work index (RVSWI) were also associated with RVF. Using receiver operating characteristic curve-derived cut-points, PAPi < 1.85 provided 94% sensitivity and 81% specificity (C-statistic = 0.942) for identifying RVF and exceeded the predictive value of RA:PCWP, RVSWI, or RA pressure alone. CONCLUSIONS PAPi is a simple hemodynamic variable that may help to identify patients at high risk of developing RVF after LVAD implantation.

Eptifibatide for the Treatment of HeartMate II Left Ventricular Assist Device Thrombosis

Left ventricular assist device (LVAD) thrombosis is a life-threatening complication occurring in ≈6% of patients receiving a HeartMate II (HMII) LVAD (Thoratec Corp, Pleasanton, CA) within 24 months after implantation.1 Prophylactic therapy with aspirin and warfarin to an international normalized ratio (INR) of 1.5 to 2.5 is recommended to prevent LVAD thrombosis in most HMII recipients.2 For device malfunction because of pump thrombosis, surgical device exchange may be necessary but carries a high risk of morbidity and mortality. Alternate treatment approaches include the addition of clopidogrel, tirofiban, and thrombolysis.3 We report our experience with eptifibatide (Merck & Co, Inc, Whitehouse Station, NJ), a platelet glycoprotein IIb/IIIa receptor inhibitor, for the treatment of LVAD thrombosis in 2 patients. A 66-year-old male with ischemic cardiomyopathy who underwent HMII implantation as a bridge to cardiac transplantation developed LVAD thrombosis 42 days after his surgery while taking 325 mg of aspirin and warfarin. His INR was subtherapeutic at 1.3. Hematuria, a lactate dehydrogenase level of 2326 IU/L, direct bilirubin of 0.8 mg/dL, a lower pulsatility index, and pump flow compared with previous levels, which suggested hemolysis and …

Evaluation of myocardial mechanics with three- dimensional speckle tracking echocardiography in heart transplant recipients: comparison with two-dimensional speckle tracking and relationship with clinical variables

AIMS Two-dimensional speckle-tracking echocardiography (2D-STE) is limited by its inability to track tissue motion in three dimensions. This is particularly relevant in heart transplant recipients, in whom marked translational motion of the transplanted heart is present. We aimed to compare 3-dimensional (3D)- and 2D-STE-derived strain parameters, and to identify clinical features associated with myocardial mechanics in transplant recipients. METHODS AND RESULTS In 36 heart transplant recipients, global and regional left-ventricular (LV) longitudinal and circumferential strain (LSt and CSt), and radial displacement (RDisp) were obtained by 3D- and 2D-STE, and their results were compared. 3D-STE deformation from a subset of transplant recipients with preserved ejection fraction was compared with a control group of 25 subjects matched by gender, age, history of hypertension, and ejection fraction. Associations between global LSt and CSt and clinical, echocardiographic, and haemodynamic parameters in transplant recipients were investigated. 3D-STE yielded lower magnitude of global LSt compared with 2D-STE (-13 ± 3 vs. -16 ± 3%, P < 0.001). The inferolateral wall was a source of variation between 3D- and 2D-STE both for LSt and CSt. Inferolateral wall 3D-STE-derived RDisp was greater than that observed in control subjects (7.4 ± 1.2 vs. 6.5 ± 1.7 mm, P = 0.03), while anteroseptal RDisp was lower than controls (4.2 ± 1.0 vs. 7.3 ± 1.6 mm, P < 0.001). Multiple regression analysis demonstrated that 3D-STE-derived LSt was independently associated with NYHA class (P < 0.001), while 2D-STE-derived LSt was not. CONCLUSION Examination of LV mechanics by 3D- and 2D-STE deformation parameters in heart transplant recipients yields significantly discordant results. 3D-STE-derived LSt is independently associated with NYHA class, suggesting a clinically important relationship between functional status and myocardial mechanics.