Naveen L. Pereira

Echocardiographic Variables Post LVAD Associated with Adverse Outcome

Background— Operative mortality after left ventricular assist device (LVAD) implantation is heavily influenced by patient selection and the technical difficulty of surgery. However, how we treat our patients and LVAD setting may affect the patient outcome beyond this period. We postulated that the presence of echocardiographic variables 1 month after surgery suggesting appropriate degree of LV unloading and an adequate forward flow would be important in determining clinical outcomes after the initial successful LVAD implantation. Methods and Results— We retrospectively analyzed various variables in echocardiographic examinations performed 30 days after LVAD implant in 76 consecutive patients receiving continuous flow device for their association with a compound end point (90-day mortality, readmission for heart failure, or New York Heart Association class III or higher at the end of the 90-day period). The echocardiographic associations examined included estimated LVAD flow, with and without native LV contribution, interventricular septal position, the status of aortic valve opening, an estimated left atrial pressure (ELAP), the mitral flow E-wave deceleration time, and the ratio of deceleration time to E-wave velocity (mitral deceleration index [MDI]). Four patients died during the 30- to 90-day period, 6 patients were readmitted for heart failure, and 25 patients were considered to have New York Heart Association class III or higher at the end of the 90-day period. Variables associated with adverse outcome included increased ELAP (odds ratio, 1.30 [1.16–1.48]; P<0.0001), MDI <2 ms/[cm/s] (odds ratio, 4.4 implantation [1.22–18]; P=0.02) and decreased tricuspid lateral annulus velocity (odds ratio, 0.70 implantation [0.48–0.95]; P=0.02). A leftward deviation of interventricular septum was associated with a worse outcome (odds ratio, 3.03 implantation [1.21–13.3]; P=0.01). Conclusions— Mortality and heart failure after LVAD surgery appear to be predominantly determined by echocardiographic evidence of inefficient unloading of the left ventricle and persistence of right ventricular dysfunction. Increased estimated LA pressure and short MDI are associated with worse mid term outcome. Leftward deviation of the septum is associated with worse outcome as well.Background —Operative mortality following LVAD implantation is heavily influenced by patient selection and the technical difficulty of surgery. However, how we manage our patients and LVAD setting may affect the patient outcome beyond this period. We postulated that the presence of echocardiographic variables one month after surgery suggesting appropriate degree of LV unloading and an adequate forward flow would be important in determining clinical outcomes following the initial successful LVAD implantation. Methods and Results —We retrospectively analyzed various variables in echocardiographic examinations performed 30 days after LVAD implant in 76 consecutive patients receiving continuous flow device (Heart Mate II) for their association with a compound endpoint (90 day mortality, re-admission for heart failure, or NYHA≥III at the end of the 90 day period). The echocardiographic associations examined included estimated LVAD flow, with and without native LV contribution, inter-ventricular septal position, the status of aortic valve opening, an estimated left atrial pressure (ELAP), the mitral flow E wave deceleration time and the ratio of deceleration time to E wave velocity (mitral deceleration index [MDI]). Four patients died during the 30-90 day period, six patients were re-admitted for heart failure, and 25 patients were considered to have NYHA≥III at the end of the 90 day period. Variables associated with adverse outcome included increased ELAP (Odds Ratio (OR) 1.30(1.16-1.48); p<0.0001), MDI<2 ms/ [cm/s] (OR 4.4(1.22-18); P=0.02) and decreased tricuspid lateral annulus velocity (OR 0.70(0.48-0.95); P=0.02). A leftward deviation of inter-ventricular septum was associated with a worse outcome (OR 3.03(1.21-13.3); P=0.01). Conclusions —Mortality and heart failure after LVAD surgery seem to be predominantly determined by echocardiographic evidence of inefficient unloading of left ventricle and persistence of RV dysfunction. Increased estimated LA pressure and short MDI are associated with worse mid term outcome. Leftward deviation of the septum is associated with worse outcome as well.

Transthoracic real-time three-dimensional echocardiography in the diagnosis and description of noncompaction of ventricular myocardium.

Background: Numerous modalities have been used to diagnose and characterize noncompaction of ventricular myocardium (NCVM) including magnetic resonance imaging, two‐dimensional echocardiography (2DE), contrast‐enhanced 2DE, and angiography. The current case series examines the use of real‐time three‐dimensional transthoracic echocardiography (RT‐3DE) in four such cases of NCVM. Methods: From December 2003 to March 2004, we performed RT‐3DE using a Philips Sonos 7500 echocardiographic scanner equipped with a 2–4 MHz 3D matrix array transthoracic probe, to evaluate four patients with NCVM. The real‐time 3D transthoracic probe allows for dataset acquisition in an ultrasound wedge, which can be manipulated instantaneously. In addition, complete 3D volume rendering is acquired, allowing for volumetric imaging. Results: The age range of the patients was 2 months to 42 years. One patient had the codiagnoses of coarctation of the aorta and bicuspid aortic valve. In all four patients, RT‐3DE enabled diagnosis and provided detailed characterization of the affected myocardium. Entire trabecular projections and intertrabecular recesses were easily visualized simultaneously, and endocardial borders were clearly demarcated. Wall motion abnormalities of the affected myocardium were clearly visualized. The compacted and noncompacted portions of the myocardium could be differentiated well. Conclusions: Our study provides preliminary data highlighting the utility and feasibility of RT‐3DE in the clinical characterization of NCVM. The complex 3D nature of this disorder and the endocardial hypertrabeculation were more readily visualized than with 2DE.

The role of medical management for acute intravascular hemolysis in patients supported on axial flow LVAD.

Continuous flow left ventricular assist devices (LVADs) are used with good outcome. However, acute intravascular hemolysis due to thrombus in the pump remains a clinical challenge. We screened for LVAD-related intravascular hemolysis among 115 consecutive patients surviving HeartMateII implantation and investigated the role of medical therapy in resolving the hemolysis. Hemolytic events were identified in 7% of patients, 2–26 months after implant, manifested by peak lactate dehydrogenase (LDH) levels >6 times normal. With the institution of heparin and enhanced antiplatelet therapy, LDH levels receded rapidly reaching a stable trough level near baseline within 2 weeks with the resolution of clinical symptoms except in one patient who required additional therapy with tissue plasminogen activator (tPA). Complications included transient renal failure, one splenic infarct, and a cerebrovascular attack after tPA. The acute event of hemolysis resolved with medical therapy, and all were successfully discharged. However, recurrent hemolysis was common (6/8 patients over the next 1–7 months). At the end of follow-up, three patients were transplanted, one patient died refusing LVAD exchange for recurrent hemolysis, and 4 remained alive on LVAD support. Medical treatment with intensification of anticoagulation can be effective in resolving the acute hemolytic event. However, a definitive long-term strategy should be planned because the recurrence rate is high.

LVAD implant as a bridge to heart transplantation is associated with allosensitization as measured by single antigen bead assay.

Background Left ventricular assist devices (LVAD) as a bridge (BTT) to heart transplantation (HTX) may be limited by the formation of anti–human leukocyte antigen antibodies. Whether sensitization occurs with continuous axial flow LVAD implant as assessed by single antigen bead (SAB) assay is unknown. Methods Cytotoxic panel-reactive antibody (PRA) and SAB assays were analyzed in HTX recipients undergoing LVAD implant as a BTT. Sensitization was defined as peak anti–human leukocyte antigen antibody values of more than 2000 mean fluorescence intensity because these values have been found to correlate with flow cytometric crossmatch results. Results LVADs were implanted as BTT in 30 patients. There were 7% (2 of 30) of patients before LVAD implant and no patients after LVAD implant with PRA more than 10%. However, 20% (6 of 30) of patients before LVAD and 53% (16 of 30) after LVAD were sensitized as measured by SAB (P=0.024). At HTX, 47% (14 of 30) of patients remained sensitized. A positive virtual crossmatch was observed in 28% (4 of 14) of the sensitized patients at HTX. There was no difference between the sensitized and nonsensitized groups (P>0.4 for all) in usage of blood products (6411 vs. 6339 units) and time to HTX (28,663 vs. 25,748 days), and 1 year after HTX, there were no differences in rejection (total rejection score 0.30 vs. 0.37) and survival (93% vs. 88%). Conclusion Allosensitization after LVAD is common despite cytotoxic PRA being negative. One year after HTX, this sensitization does not translate into increased acute cellular or antibody-mediated rejection or reduced survival.

Combined heart and liver transplantation: protection of the cardiac graft from antibody rejection by initial liver implantation.

A 50-year-old Caucasian female with arrhythmogenic right ventricular (RV) dysplasia presented with 2 years of progressive RV heart failure (New York Heart Association class IV), recurrent ascites, and peripheral edema in spite of optimal medical therapy. Liver biopsy demonstrated advanced liver cirrhosis. Left ventricular chamber size and systolic function were normal. Right heart catheterization was consistent with severe RV dysfunction (RV dP/dtG200 mm Hg/ms). The patient had had three pregnancies. Surgical history included surgical disarticulation of the right ventricle for recurrent syncope, and a cholecystectomy a few months before presentation, requiring transfusion of blood products. She was found to have a large number of antiYhuman leukocyte antigen (HLA) antibodies with very high titers (Fig. 1A). The cytotoxic panel reactive antibody (PRA) was positive at 98%. The ‘‘calculated’’ PRA based on existing antiHLA antibodies with levels above 8000 mean fluorescence intensity was 95%. She was blood group A, Rh positive. It was thought that an appropriate donor for cardiac transplantation was not likely and that usual desensitization protocols would be insufficient in the context of very high PRA and very high antibody titers. Based on our experience with renal transplantation in recipients with donor-specific antibody (DSA) (1, 2), we planned to proceed with liver followed by heart transplantation with the use of a single local donor (G200 miles) to minimize cardiac ischemic time and perform a prospective flow-mediated crossmatch accepting a positive T-cell crossmatch with a channel shift less than 350 or a positive complement-dependent cytotoxicity crossmatch up to a dilution of 1:8. The plan also consisted of performing preoperative plasmapheresis and intravenous eculizumab (3), intended to protect the heart until the liver had time to reduce the DSA levels. The donor was an 18-year-old African-American male who suffered a gunshot wound to the head. The heart and liver were felt suitable for transplantation. Donor and recipient HLA types are shown in Table S1 (see SDC, http://links.lww.com/TP/A739). DSA are shown in Figure 1B (pre-Tx). Prospective cytotoxic crossmatch was negative. Flow crossmatch was positive with channel shifts for B-cell FCXM 358 and T-cell FCXM 279. Preoperative plasmapheresis was performed, methylprednisolone (360 mg) was given intravenously, and the first dose of eculizumab (1200 mg) was administered after which DSA titers were rechecked (Fig. 1B, post-PP). To minimize cardiac ischemic time and to allow cardiopulmonary bypass to be initiated at the time of liver reperfusion, the initial step of the surgical procedure was median sternotomy and dissection of aorta and superior and inferior vena cava. The liver transplant team then performed the abdominal incision and dissection for the liver transplantation. Before reperfusion of the liver, heparin was administered, cannulas were placed in the vena cavas and ascending aorta, and cardiopulmonary bypass was initiated to reduce hepatic venous pressure for the liver (set at 2.4 L/min/m). The patient was cooled to 32-C, and mean systemic blood pressure was maintained at above 70 to 80 mm Hg to adequately perfuse the liver. After hepatic reperfusion, methylprednisolone (250 mg) was given and blood was drawn for repeat crossmatch (Fig. 1B, post-liver). A second dose of eculizumab (1200 mg) was administered. Cardiac dissection and cardiectomy were performed and cardiac implantation was performed in a standard fashion with bicaval anastomoses. The cardiac ischemic time was 4 hr 17 min. After weaning from cardiopulmonary bypass and giving protamine to reverse the heparin, methylprednisolone (500 mg) was administered followed 30 min later by rabbit anti-thymocyte globulin (110 mg; our standard immunosuppression for heart transplantation). A third dose of eculizumab (900 mg) was given 9 hr after the second dose and after the patient had arrived in the intensive care unit. Flow crossmatch was repeated with donor serum and blood was drawn from the recipient immediately after the transplantation and was negative for both B and T cells (channel shift G52 for B cells and G106 for T cells). Anti-HLA antibody titers were monitored daily, showing a significant decrease immediately after liver transplantation, and stabilization since then (Fig. 1B). Based on this, no additional doses of eculizumab were given and no additional plasmapheresis (just one time preoperatively) was performed. Immunosuppression was managed routinely with induction therapy using daily anti-thymocyte globulin (seven doses) until initiation of tacrolimus (based on renal function) and until therapeutic levels were achieved. The first cardiac biopsy was at the time of chest closure 2 days after transplantation and was negative for celland antibody-mediated rejection. In the 15 months after surgery, she has had more than 10 sequential cardiac biopsies that were all negative for cellor antibody-mediated rejection. Anti-HLA antibodies were monitored routinely twice a week and have remained stable (Fig. 1B). At 15 months after transplantation, she has done very well clinically with no other complications and regained normal functional status with no recurrent edema or ascites. LETTERS TO THE EDITOR

TPMT genetic variants are associated with increased rejection with azathioprine use in heart transplantation.

Objectives Azathioprine (AZA) is an important immunosuppressant drug used in heart transplantation (HTX). Consensus guidelines recommend that patients with thiopurine S-methyltransferase (TPMT) genetic variants be started on lower AZA dose because of higher active metabolite levels and risk of adverse events. However, in-vitro lymphocyte proliferation assays performed in participants with inactive TPMT alleles have suggested that AZA use may result in decreased immunosuppressant efficacy as compared with wild-type (WT) individuals. The objective of this study was therefore to determine the effect of TPMT genetic variation on AZA efficacy or prevention of rejection in HTX recipients treated with AZA. Participants and methods We genotyped 93 HTX recipients treated with AZA and measured erythrocyte TPMT enzyme activity. Acute rejection was monitored by routine endomyocardial biopsies. Results There were 83 WT and 10 heterozygote (HZ) HTX recipients. TPMT activity level was lower in HZ compared with WT (13.1±2.8 vs. 21±4.5 U/ml red blood cell, P<0.001). Despite similar AZA dose, HZ developed severe rejection earlier (P<0.001), and the total rejection score was higher (P=0.02) than WT. AZA was discontinued more frequently in HZ (P=0.01) because of rejection. The incidence of leukopenia was similar between the groups (40 vs. 43%, P=1.0). Conclusion HTX recipients with TPMT genetic variant alleles who are treated with AZA develop acute rejection earlier, more frequently, and of greater severity. These patients, despite having lower TPMT enzymatic activity, should be monitored carefully for possible increased risk of acute rejection.

The role of donor-specific antibodies in acute cardiac allograft dysfunction in the absence of cellular rejection

Background Acute allograft dysfunction (AAD) is an important cause of morbidity among heart transplant recipients. The role of donor-specific antibodies (DSAs) in AAD, with the increasing use of single antigen bead (SAB) assays that have improved the ability to detect DSA, remains unclear. Methods We retrospectively reviewed 329 heart transplant recipients followed up at our institution. AAD was defined as an acute decline in left ventricular ejection fraction to less than 50% and a decrement of 10% or higher compared to baseline in the absence of cellular rejection. Patients with AAD were compared with matched 30 heart transplant controls. Results There were 10 (3%) patients with AAD, 4 (40%) had DSA detectable by SAB assay compared to 16 (53%) controls (P=0.43). Peak DSA mean fluorescent intensity (MFI) levels were significantly higher at baseline (class I and class II) in AAD compared to controls. DSA MFI values increased at the time of AAD and returned to baseline values during follow-up for these patients with AAD (P<0.05) but remained unchanged over time for controls. Six (60%) patients with AAD and 1 (3%) control had antibody-mediated rejection (AMR) by endomyocardial biopsy (P<0.01). There were 4 (40%) patients with AAD with no DSA or AMR. Conclusions AAD after heart transplant is a heterogeneous process characterized by 1) AMR and DSA, 2) AMR but no DSA, and 3) no AMR or DSA. The presence of DSA is not associated with AAD, but the quantity assessed by MFI levels may play a role.

Early Gains in Renal Function Following Implantation of HeartMate II Left Ventricular Assist Devices May not Persist to One Year

Renal function improves early after left ventricular assist device (LVAD) implantation but later decline has been observed. We sought to determine the occurrence and evaluate possible causes for this decline. In 62 consecutive patients with HeartMateII LVAD with available calculated glomerular filtration rate (GFR, ml/min/1.73 m2) 1 year after implant, GFR was assessed repeatedly and possible predictors for decline from 3 to 12 months were investigated. Post-mortem renal specimens for patients supported with an LVAD were evaluated. GFR 54.5 ± 19.5 at admission increased to 66.4 ± 22.3 preoperatively and to 79.2 ± 30.1 ~1 month after implantation. Subsequently at ~3 months GFR declined to 74.7 ± 25.4, at ~6 months to 68.8 ± 23.1, and ~1 year after implant to 63.9 ± 17.7. Glomerular filtration rate at 1 year was significantly lower (p < 0.0001, p < 0.0001, p = 0.005) than GFR 1, 3, and 6 months after implant. Early rise in GFR after surgery was not associated with late decline. Shorter bypass time (&bgr; = −0.09, p = 0.048) and higher albumin 3 months after LVAD (&bgr; = 14.4, p = 0.025) were significantly associated with less later decline in GFR. Arteriosclerosis was identified in autopsy renal specimens. In conclusion, early gains in renal function after LVAD implant are not sustained in many patients. Patient, device, and operative factors may influence long-term renal function in these patients.

Systolic heart failure: practical implementation of standard guidelines.

Congestive heart failure (CHF) is being described as an epidemic of the next decade. Despite significant advances in the treatment of systolic heart failure, community mortality remains high, which is partly due to a failure to implement standard guidelines. The purpose of this article is to describe the scope of the problem, advances in pathophysiology, common clinical scenarios, and practical implementation of standard therapies for CHF.

Timing of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor initiation and allograft vasculopathy progression and outcomes in heart transplant recipients: Timing of statins and cardiac allograft vasculopathy

Early studies from the 1990s have shown that statins improve survival and attenuate cardiac allograft vasculopathy (CAV). However, little contemporary data are available on the incremental benefit of statins with the current use of new‐generation immunosuppressive agents and the use of coronary intravascular ultrasound for assessment of CAV. We sought to investigate the effect of early statin (ES) as compared with late statin (LS) initiation after heart transplantation (HT) on long‐term CAV progression and clinical outcomes in a large contemporary HT cohort.