Heart-liver-kidney transplantation for AL amyloidosis using normothermic recovery and storage from a donor following circulatory death: Short-term outcome in a first-in-world experience.

AL amyloidosis is a rare condition characterized by the overproduction of an unstable free light chain, protein misfolding and aggregation, and extracellular deposition that can progress to multiorgan involvement and failure. To our knowledge, this is the first worldwide report to describe triple organ transplantation for AL amyloidosis and triple organ transplantation using thoracoabdominal normothermic regional perfusion recovery with a donation from a circulatory death (DCD) donor. The recipient was a 40-year-old man with multiorgan AL amyloidosis with a terminal prognosis without multiorgan transplantation. An appropriate DCD donor was selected for sequential heart, liver, and kidney transplants via our center's thoracoabdominal normothermic regional perfusion pathway. The liver was additionally placed on an ex vivo normothermic machine perfusion, and the kidney was maintained on hypothermic machine perfusion while awaiting implantation. The heart transplant was completed first (cold ischemic time [CIT]: 131 minutes), followed by the liver transplant (CIT: 87 minutes, normothermic machine perfusion: 301 minutes). Kidney transplantation was performed the following day (CIT: 1833 minutes). He is 8 months posttransplant without evidence of heart, liver, or kidney graft dysfunction or rejection. This case highlights the feasibility of normothermic recovery and storage modalities for DCD donors, which can expand transplant opportunities for allografts previously not considered for multiorgan transplantations.

Factors influencing transfusion-associated HLA sensitization in patients bridged to heart transplantation using ventricular assist device.

BACKGROUND: Bridging heart failure patients with mechanical ventricular assist devices (VAD) enables access to transplantation. However, VAD is associated with increased risk for anti-HLA antibodies associated with rejection of subsequent allografts. Factors determining alloantibody formation in these patients remain undefined. METHODS: We performed a single-center retrospective cohort study of 164 patients undergoing heart transplantation from 2014 to 2017. Medical records including use of VAD, transfused blood products, anti-HLA antibody testing, crossmatch, and time to transplant were evaluated. RESULTS: Patients received an average of 13.8 red blood cell and 1.9 single-donor platelet units associated with VAD. There was a 28.7% increase in the incidence of anti-HLA antibodies after VAD. Development of anti-HLA antibodies did not correlate with volume or type of blood products, but with pre-VAD HLA sensitization status; relative risk of new alloantibodies in patients with pre-VAD antibodies was 3.5-fold higher than those without prior antibodies (P = .008). Development of new anti-HLA antibodies was associated with an increased time to transplant (169 vs 330 days, P = .013). CONCLUSIONS: Our findings indicate that the presence of anti-HLA antibodies pre-VAD was the most significant risk factor for developing additional antibodies post-VAD, suggesting that a subset of patients may be predisposed to alloantibody formation.

Heart transplantation outcomes for rheumatic heart disease: Analysis of international registry data.

BACKGROUND: Rheumatic heart disease (RHD), an autoimmune sequela of Group A streptococcal infection, is a chronic valvular disease affecting 32 million people worldwide, predominantly in developing nations. As the predisposition to autoimmune sequela still remains post transplantation, our primary objective was to assess if there were differences in mortality and rejection rates. METHODS AND RESULTS: Using the International Society for Heart and Lung Transplantation (ISHLT) adult heart transplant registry, we identified 42 RHD patients who had undergone heart transplantation between 1988 and 2014. We matched the 42 RHD recipients by transplant year, age, and gender to 420 dilated cardiomyopathy (DCM) recipients. One-year mortality in the RHD group was 17.95% vs. 7.92% in the DCM group (P = 0.07). Survival was significantly reduced in the RHD group vs. the DCM group via Kaplan Meier curves (P = 0.04). In a multivariate model, RHD status (OR 3.19, 95% CI 1.15-8.83, P = 0.025) and serum creatinine (OR 1.41, 95% CI 1.09-1.82, P = 0.009) were associated with an increased odds of one-year mortality (P = 0.0013). CONCLUSIONS: At one year post transplantation, RHD recipients had a significantly lower survival than DCM recipients. RHD status was also an independent predictor of mortality at 1 year post transplantation.

Transitioning disopyramide to mavacamten in obstructive hypertrophic cardiomyopathy: A case series and clinical guide.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic disorder for which first-line treatments for obstructive HCM (oHCM) include beta-blockers, non-dihydropyridine calcium channel blockers, and disopyramide for refractory cases. Mavacamten, a selective cardiac myosin inhibitor, is indicated for symptomatic oHCM to improve functional capacity and symptoms. Use of disopyramide and mavacamten together is not recommended due to concerns of additive negative inotropic effects. Transitioning from disopyramide to mavacamten may be preferred to avoid adverse effects and frequent administration, however, the best approach for making the transition has not been established. CASES: We present a series of seven patients with oHCM who transitioned from disopyramide to mavacamten and underwent echocardiograms mandated by a Risk Evaluation and Mitigations Strategies program. Two methods were employed. The first approach, involving washout of disopyramide before starting mavacamten, resulted in worsening of heart failure symptoms in the first two cases. The second approach, involving tapering disopyramide when starting mavacamten, was successfully implemented in the last five cases, with no adverse effects or worsening of systolic dysfunction. CONCLUSION: Our method of tapering disopyramide when starting mavacamten using a stepwise approach is feasible and safe. Our report fulfills an unmet need by serving as a guide for other clinicians who seek to transition their patients from disopyramide to mavacamten.

Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics.

All muscle contraction occurs due to the cyclical interaction between sarcomeric thin and thick filament proteins within the myocyte. The thin filament consists of the proteins actin, tropomyosin, Troponin C, Troponin I, and Troponin T. Mutations in these proteins can result in various forms of cardiomyopathy, including hypertrophic, restrictive, and dilated phenotypes and account for as many as 30% of all cases of inherited cardiomyopathy. There is significant evidence that thin filament mutations contribute to dysregulation of Ca2+ within the sarcomere and may have a distinct pathomechanism of disease from cardiomyopathy associated with thick filament mutations. A number of distinct clinical findings appear to be correlated with thin-filament mutations: greater degrees of restrictive cardiomyopathy and relatively less left ventricular (LV) hypertrophy and LV outflow tract obstruction than that seen with thick filament mutations, increased morbidity associated with heart failure, increased arrhythmia burden and potentially higher mortality. Most therapies that improve outcomes in heart failure blunt the neurohormonal pathways involved in cardiac remodeling, while most therapies for hypertrophic cardiomyopathy involve use of negative inotropes to reduce LV hypertrophy or septal reduction therapies to reduce LV outflow tract obstruction. None of these therapies directly address the underlying sarcomeric dysfunction associated with thin-filament mutations. With mounting evidence that thin filament cardiomyopathies occur through a distinct mechanism, there is need for therapies targeting the unique, underlying mechanisms tailored for each patient depending on a given mutation.

Selective and specific regulation of ectodomain shedding of angiotensin-converting enzyme 2 by tumor necrosis factor alpha-converting enzyme.

Angiotensin-converting enzyme 2 (ACE2) is a newly identified regulator of the renin-angiotensin system. This type I membrane-anchored protein has a catalytically active ectodomain that undergoes shedding. Tumor necrosis factor alpha-converting enzyme (TACE) has been shown to be involved in ACE2 shedding. Although pathophysiological significance of ACE2 shedding has been suggested, regulation of this process by TACE is not clearly defined. We characterized TACE-mediated constitutive ectodomain shedding of ACE2 using wild-type Chinese Hamster Ovary (WT-CHO), the TACE-mutant M2 (M2-CHO) cells, and EC-4 and EC-2 cells that are fibroblasts from wild-type and TACE-null mice, respectively. ACE2 was constitutively cleaved to release two distinct major soluble forms. The deglycosylated molecular masses of the larger (LSF) and smaller soluble form (SSF) were approximately 80 and 70 kDa, respectively. These forms had equivalent enzyme activities. Reduced shedding for the LSF from M2-CHO and EC-2 cells when compared with WT-CHO and EC-4 cells, respectively, was noted. TACE reconstitution in EC-2 cells expressing ACE2 resulted in increase in LSF but not SSF release, demonstrating a main role of TACE in LSF release and distinct regulations of release of the two soluble forms. Deletions of the juxtamembrane region of ACE2 reduced LSF release in CHO cell lines, whereas it abolished TACE-induced shedding in EC-2 cells. Analysis of TACE structural domains confirmed that the active site in the catalytic domain is essential for ACE2 shedding but that noncatalytic domains also play additional roles. These results demonstrate selective and specific regulation of constitutive shedding of ACE2 by TACE.

Management of RVAD Thrombosis in Biventricular HVAD Supported Patients: Case Series.

Patients with biventricular assist devices (BIVAD) are severely critically ill compared with patients who receive left ventricular assist device (LVAD) support alone and portend a significant risk for greater adverse events including pump thrombosis (PT). Current approaches to treat PT are limited to LVAD with variable outcomes depending on the management strategy implemented. Moreover the management of PT in patients with BIVAD support, specifically to the right ventricular assist device (RVAD), is unknown. We describe the first care series to date on the management of PT in patients with durable right ventricular assist device and their outcomes.

Which advanced heart failure therapy strategy is optimal for patients over 60 years old?

BACKGROUND: The optimal advanced heart failure (HF) therapy strategy for patients aged 60 or older with end-stage HF refractory to optimal medical therapy remains uncertain. This study compares outcomes of three advanced HF therapy strategies in this patient population. METHODS: A single-center retrospective study was conducted in 95 patients aged 60-73 years who had undergone isolated heart transplantation (HTx) or continuous flow left ventricular assist device (LVAD) implantation from 2010 to 2017. Patients were stratified into three cohorts by strategy; HTx-only (N.=25), LVAD-to-HTx (N.=29), and LVAD-only (N.=41). Primary end point was 2-year overall survival. Secondary end points included incidence of post-operative adverse events, freedom from first readmission at 1 year, and percentage of days spent in hospital following advanced HF therapy. RESULTS: Two-year survival was 91% in HTx-only patients, 88% in LVAD-to-HTx patients, and 49% in LVAD-only patients (P=0.0008). No significant difference in post-transplant survival was found between patients with or without LVAD-related adverse events preceding transplantation (P=0.42). One-year freedom from first readmission was 38.3% in HTx-only patients, 17.2% in LVAD-to-HTx patients and 7.3% in LVAD-only patients (P=0.0028). Patients in LVAD-to-HTx cohort had higher incidences of gastrointestinal bleeding (38% vs. 3%; P<0.01), major bleeding (28% vs. 3%; P=0.02), and right heart failure (69% vs. 31%; P<0.01) during post-LVAD period compared with post-HTx period. Their percentage of days spent in hospital during post-LVAD period was significantly higher than post-HTx period (7.9% vs. 1.2%; P<0.001). CONCLUSIONS: Our experience with patients over 60 years old undergoing advanced therapy suggests that HTx-only and LVAD-to-HTx strategies had superior medium-term survival than LVAD-only strategy. LVAD-to-HTx strategy is effective in reducing incidence of adverse events and percentage of hospitalized days in this specific patient population.

Durable Biventricular Support Using Right Atrial Placement of the HeartWare HVAD.

Patients with Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) levels 1-2 who either have or are at risk for right ventricular failure face significant morbidity and mortality after continuous flow left ventricular assist device (CF-LVAD) implantation. Currently, the options for biventricular support are limited the Total Artificial Heart (TAH; CardioWest, Syncardia, Tuscon, AZ) or biventricular assist device (BiVAD), which uses bulky extracorporeal or implantable displacement pumps. We describe a successful series based on an innovative approach for biventricular support in consecutive INTERMACS levels 1-2 patients utilizing a HeartWare Ventricular Assist Device (HVAD; HeartWare, Framingham, MA) in a left ventricular (LV-HVAD) and a right atrial (RA-HVAD) configuration. From June 2014 through May 2016, 11 consecutive INTERMACS levels 1-2 patients with evidence of biventricular failure underwent implantation of a CF LVAD (10 LV-HVAD and 1 HeartMate II LVAD, Thoratec, Pleasanton, CA) and RA-HVAD pumps. A total of 4,314 BiVAD support days were accumulated in our case series. Seven patients have undergone orthotopic heart transplant, whereas 3 are ambulatory and are either waiting transplant or reconsideration for transplantation. There is one mortality in this case series, which was due to an intracranial bleed from supratherapeutic anticoagulation. Two other patients experienced hemorrhagic strokes, but without neurologic sequelae, whereas no patients have experienced ischemic strokes. There were two episodes of gastrointestinal bleeding. This is the largest series to date involving this approach with outcomes superior to those previously described in patients receiving biventricular support. We conclude this novel therapy is a viable alternative to current practices in the management of biventricular failure.

Mechanical Circulatory Support: Current Status and Future Directions.

Advance heart failure (AHF) is a growing epidemic with high morbidity and mortality. Left ventricular assist device (LVAD) has come to offer an opportunity to improve survival and quality of life. This form of therapy however, is not free of complications and poses a challenge to apply to a broader population. Adjunct therapies in combination with LVAD therapy and advances in device technology are in the near future, which may lessen the number of adverse events. This review summarizes the history, clinical outcomes and current challenges facing LVAD therapy. Finally, future directions of LVADs in the treatment of AHF are discussed.

Effect of peripheral vascular disease on mortality in cardiac transplant recipients (from the United Network of Organ Sharing Database).

Peripheral vascular disease (PVD) portends increased morbidity and mortality in patients with heart failure. In those with advanced heart failure, heart transplantation (HT) is the only causative therapy to increase survival. However, little is known about the impact of symptomatic PVD on survival of HT recipients in large multicenter cohorts. The aim of this study was to investigate an association between recipient symptomatic PVD and survival after HT. We analyzed 20,297 patients from the United Network of Organ Sharing data set. Survival analysis using a control cohort established by propensity matching was performed. There was an increased prevalence of traditional cardiovascular risk factors in 711 patients with symptomatic PVD compared with 19,586 patients without PVD. Patients with pretransplant symptomatic PVD had increased post-transplant mortality compared with those without PVD (1-, 5- and 10-year survival rate 91.5% vs 94.9%, 74.8% vs 82.6%, 48.6% vs 54.7%, respectively, log-rank p<0.001). On multivariate analysis based on the propensity matching, factors associated with a lower survival rate were presence of PVD (hazard ratio 1.20, 95% confidential interval 1.02 to 1.42, p=0.030), and female gender (hazard ratio 1.22, 95% confidence interval 1.02 to 1.47, p=0.034). In conclusion, patients with symptomatic PVD have a lower survival rate after HT. Symptomatic PVD should be considered an independent risk factor for poor prognosis in patients undergoing HT evaluation.

Inotropic contractile reserve can risk-stratify patients with HIV cardiomyopathy: a dobutamine stress echocardiography study.

OBJECTIVES: The purpose of this study was to assess whether inotropic contractile reserve (ICR) during dobutamine stress echocardiography (DSE) could risk-stratify patients with human immunodeficiency virus (HIV) cardiomyopathy and predict improvement of left ventricular ejection fraction (LVEF). BACKGROUND: HIV cardiomyopathy is an important cause of heart failure and death. ICR is associated with better survival and improvement of LVEF in patients with ischemic and nonischemic cardiomyopathies. However, the prognostic value of ICR in patients with HIV cardiomyopathy is unknown. METHODS: Patients with HIV cardiomyopathy and a LVEF <45% who were referred for DSE were enrolled. ICR was evaluated by the delta wall motion score index (ΔWMSI), calculated as the difference between rest and peak WMSI. Patients were followed for cardiac death and change in LVEF on follow-up. RESULTS: Sixty patients (75% men; age, 54 ± 9 years) with HIV cardiomyopathy (mean LVEF, 28 ± 11%) formed the study group. After 2.4 ± 2.1 years, 11 cardiac deaths occurred (event rate of 7.6%/year). A receiver-operating characteristic curve identified a ΔWMSI of 0.38 as an optimal cut point for the presence of ICR, with a specificity of 88% and a sensitivity of 73% for the prediction of cardiac death. On univariable analysis, the absence of ICR (hazard ratio: 6.6; 95% confidence interval: 1.93 to 22.62; p = 0.003) and New York Heart Association functional class IV (hazard ratio: 7.2; 95% confidence interval: 2.20 to 23.65; p = 0.001) were the only predictors of cardiac death. After 2.1 ± 1.8 years, 41 patients had a follow-up echocardiogram. LVEF improvement from baseline occurred in 23 patients (56%), more so in patients with ICR than without ICR. A ΔWMSI of 0.59 predicted improvement in the LVEF with a specificity of 78% and a sensitivity of 74%. CONCLUSIONS: The presence of ICR during DSE can risk-stratify and predict subsequent improvement in LVEF in patients with HIV cardiomyopathy.

Risk stratification and prognosis of human immunodeficiency virus-infected patients with known or suspected coronary artery disease referred for stress echocardiography.

BACKGROUND: Patients with human immunodeficiency virus (HIV) infection are at increased risk of accelerated coronary artery disease (CAD) and cardiovascular events. Stress echocardiography (SE) is routinely used for risk stratification and prognosis of patients with known or suspected CAD. The prognostic value of SE in this high-risk group is unknown. The purpose of this study was to evaluate the prognostic value of SE in HIV-infected patients with known or suspected CAD. METHODS AND RESULTS: We evaluated 311 patients (age, 52 ± 9 years; 74% men; left ventricular ejection fraction, 54 ± 12%) with history of HIV, undergoing SE (56% dobutamine). Left ventricular wall motion was evaluated on a 16-segment model, 5-point scale. An abnormal SE was defined by a fixed (infarction), biphasic, or new (ischemia) wall motion abnormality on stress. Follow-up for cardiac death and myocardial infarction was obtained. Seventy-nine (26%) patients had an abnormal SE. After 2.9 ± 1.9 years, 17 confirmed myocardial infarction and 14 cardiac deaths occurred. SE risk-stratified patients into normal versus abnormal subgroups (event rate, 0.6% per year versus 11.8% per year; P < 0.0001). Both abnormal SE (hazard ratio, 28.2; 95% confidence interval, 6.2 to 128.0; P < 0.0001) and the presence of any ischemia on SE (hazard ratio, 3.4; 95% confidence interval, 1.3 to 8.6; P = 0.009) were independent predictors of cardiac events. On a forward conditional Cox proportional hazards regression model, SE provided incremental prognostic value over clinical, stress ECG, and resting echocardiographic variables (global χ(2) increased from 17.8 to 24.5 to 65 to 109, P < 0.05 across all groups). CONCLUSIONS: SE can effectively risk-stratify and prognosticate patients with HIV. The presence of ischemia and scar during SE provides independent and incremental prognostic value over traditional variables. A normal SE response portends a benign prognosis even in this high-risk subset.