Alfredo L. Clavell

Readmissions after implantation of axial flow left ventricular assist device.

OBJECTIVES The purpose of this study was to determine the occurrence and causes of readmissions after implantation of axial flow left ventricular assist device (LVAD). BACKGROUND Based on the REMATCH (Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure) study experience, readmissions after LVAD implantation are thought to be frequent. METHODS We retrospectively analyzed admissions to our facility in a cohort of 115 patients implanted between January 2008 and July 2011 with the HeartMate II axial flow LVAD, of whom 42 were bridged to transplant. To account for repeated events, Andersen-Gill models were used to determine possible predictors. RESULTS The patients were followed for 1.4 ± 0.9 years. There were 224 readmissions in 83 patients. The overall readmission rate was 1.64 ± 1.97 per patient-year of follow-up. The readmission rate for the first 6 months was 2.0 ± 2.3 and decreased to 1.2 ± 2.1 during subsequent follow-up. Leading causes were bleeding (66 readmissions in 34 patients), mostly gastrointestinal bleed (51 in 27 patients), cardiac (51 in 36 patients, most for HF or arrhythmia), infections (32 in 25 patients) of which 6 were pump related, and thrombosis (20 in 15 patients) including 13 readmissions due to hemolysis. Preoperative variables associated with (fewer) readmissions in a multivariate model include residence within our hospital-extended referral zone of Minnesota and the neighboring states (hazard ratio: 0.66; 95% confidence interval: 0.48 to 0.91; p = 0.011), hemoglobin (hazard ratio: 0.91, 95% confidence interval: 0.84 to 0.99; p = 0.027) and N-terminal pro-B-type natriuretic peptide (hazard ratio: 0.98; 95% confidence interval: 0.96 to 1.0 per 1,000-unit increase, p = 0.022). C-statistic for the model: 0.63. CONCLUSIONS Readmission rates after axial flow LVAD implantation decrease during the first 6 months and then stabilize. The leading causes are bleeding, cardiac (heart failure and arrhythmia), infections, and thrombosis.

Conversion to Sirolimus as Primary Immunosuppression Attenuates the Progression of Allograft Vasculopathy After Cardiac Transplantation

Background— We investigated the potential of conversion to sirolimus (SRL) as a primary immunosuppressant in attenuating cardiac allograft vasculopathy progression. Methods and Results— Twenty-nine cardiac transplant recipients were converted to SRL 3.8±3.4 years after transplantation with complete calcineurin inhibitor (CNI) withdrawal. Secondary immunosuppressants (azathioprine or mycophenolate) and steroids remained unchanged. Forty patients (controls) 4.8±4.0 years from transplantation were maintained on CNIs. Three-dimensional intravascular ultrasound studies were performed at baseline and 12.1±2.6 months later. Mean plaque (media and intima) volume (PV) and plaque index (PI) (PV/vessel volume percent) increased significantly in the CNI group (1.28±2.86 mm3/mm, P=0.004; and 6±8%, P=0.0001) but not in the SRL group (0.1±1.13 mm3/mm, P=0.63; and 0.1±8%, P=0.94). In patients enrolled within 2 years after transplantation, the increases in PV (0.06±1.06 versus 1.77±1.65 mm3/mm; P=0.0081) and PI (0±9% versus 10±8%; P=0.0145) were smaller in the SRL group (n=11) than in the CNI (n=12) group. In patients enrolled ≥2 years after transplantation, the increase in PI was less in the SRL group compared with the CNI group (0.1±6.5% versus 5±8%; P=0.033), but changes in PV did not differ significantly. Treatment with azathioprine or mycophenolate did not affect PV or PI in either the SRL group (PV: 0.22±0.66 versus 0.05±1.45 mm3/mm, P=0.46; PI: 1.5±6% versus −1.6±8.5%, P=0.29) or the CNI group (PV: 1.42±1.39 versus 1.06±2.28 mm3/mm, P=0.49; PI: 7.8±8.7% versus 4.8±7.3%, P=0.23). Conclusions— Substituting CNI with SRL as primary immunosuppression attenuates cardiac allograft vasculopathy progression.

Changes in renal function after implantation of continuous-flow left ventricular assist devices.

OBJECTIVES The aim of this study was to determine renal outcomes after left ventricular assist device (LVAD) implantation. BACKGROUND Renal dysfunction before LVAD placement is frequent, and it is unclear whether it is due to primary renal disease or to poor perfusion. METHODS A retrospective single-center analysis was conducted in 83 consecutive patients implanted with HeartMate II continuous-flow LVADs (Thoratec Corp., Pleasanton, California). Calculated glomerular filtration rate (GFR) was assessed on admission and 1, 3, and 6 months after implantation. To define predictors for improvement in GFR, clinical variables were examined in patients with decreased renal function (GFR <60 ml/min/1.73 m(2)) before LVAD, surviving and dialysis-free at 1 month (n = 44). RESULTS GFR significantly increased from admission (53.2 ± 21.4 ml/min/1.73 m(2)) to 1 month after LVAD implantation (87.4 ± 27.9 ml/min/1.73 m(2)) (p < 0.0001). Subsequently, at 3 and 6 months, GFR remained significantly (p < 0.0001) above pre-LVAD values. Of the 51 patients with GFRs <60 ml/min/1.73 m(2) before LVAD surviving at 1 month, 34 (67%) improved to GFRs >60 ml/min/1.73 m(2). Univariate pre-operative predictors for improvement in renal function at 1 month included younger age (p = 0.049), GFR improvement with optimal medical therapy (p < 0.001), intra-aortic balloon pump use (p = 0.004), kidney length above 10 cm (p = 0.023), no treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (p = 0.029), higher bilirubin (p = 0.002), higher Lietz-Miller score (p = 0.019), and atrial fibrillation (p = 0.007). Multivariate analysis indicated pre-operative improved GFR (slope = 0.5 U per unit improved; 95% confidence interval: 0.2 to 0.8; p = 0.003), atrial fibrillation (slope = 27; 95% confidence interval: 8 to 46; p = 0.006), and intra-aortic balloon pump use (slope = 14; 95% confidence interval: 2 to 26; p = 0.02) as independent predictors. CONCLUSIONS In most patients with end-stage heart failure considered for LVAD implantation, renal dysfunction is reversible and likely related to poor renal perfusion.

Autologous Stem Cell Transplant after Heart Transplant for Light Chain (AL) Amyloid Cardiomyopathy

BACKGROUND Historically, patients with AL amyloidosis and overt congestive heart failure have had an ominous prognosis with median survival of approximately 6 months. METHODS Between 1994 and 2005, 11 patients underwent sequential orthotopic heart transplantation (HT) followed by autologous peripheral blood stem cell transplantation (SCT) for treatment of AL amyloidosis. Patients were accepted for this approach if they had heart-dominant AL with minimal/no other organ impairment and no evidence of multiple myeloma. Conditioning chemotherapy consisted of melphalan 200 mg/m(2) (6 patients) or melphalan 140 mg/m(2) (5 patients). RESULTS Two patients died of complications from the SCT (18% transplant-related mortality). Nine patients survived both the HT and the SCT. Three patients subsequently died from progressive amyloidosis at 66, 56.7 and 55 months after SCT. The 1- and 5-year survival for HT was 82% and 65%. The median survival was 76 months from HT and 57 months from SCT. CONCLUSIONS These data suggest that aggressive treatment of the underlying plasma cell clone after HT may improve long-term outcomes in patients with cardiac amyloid. HT followed by SCT is feasible and offers the possibility of remission for carefully selected patients with cardiac amyloidosis.

Combined heart and liver transplantation: A single-center experience

Background. Simultaneous combined orthotopic heart and liver transplantation (CHLTx) remains a lifesaving procedure for the patients suffering from coincident end-stage heart and liver disease and several metabolic disorders. We analyze the long-term outcome of the patients undergoing CHLTx. Methods. Between January 1992 and May 2007, 15 CHLTx were attempted at the Mayo Clinic including two combined heart, liver, and kidney transplantations and one combined heart, lung, and liver transplantations. Pretransplant cardiac diagnoses were familial amyloidosis (11), hemochromatosis (1), restrictive cardiomyopathy and cardiac cirrhosis (1), previously operated congenital heart disease and cardiac cirrhosis (1), and primary pulmonary hypertension with primary biliary cirrhosis (1). Results. Heart and liver transplantation were performed as a single combined procedure in 13 (93%) hemodynamically stable patients, and there was no perioperative mortality. Survival rates for the CHLTx recipients at 1 year, 5 years, and 10 years were 100%, 75%, and 60%, respectively, and did not differ from survival after isolated heart transplantation (93%, 83%, and 65%, respectively, P=0.39). Freedom from cardiac allograft rejection (ISHLT ≥grade 2) for CHLTx was 83% at 1 month, did not change with time, and was lower than after isolated heart transplantation (P=0.02). At the mean follow-up of 61.6±53.6 months, normal left ventricular ejection fraction and good liver allograft function were demonstrated. Three patients developed end-stage renal failure secondary to calcineurin nephrotoxicity. Conclusion. Simultaneous heart and liver transplantation is feasible and achieved excellent results for selected patients.

Acute Cellular Rejection and the Subsequent Development of Allograft Vasculopathy After Cardiac Transplantation

BACKGROUND Cardiac allograft vasculopathy (CAV) is primarily immune-mediated. We investigated the role of cellular rejection in CAV development. METHODS The study comprised 252 cardiac transplant recipients (mean age, 49.02 +/- 17.05 years; mean follow-up, 7.61 +/- 4.49 years). Total rejection score (TRS) based on the 2004 International Society of Heart and Lung Transplantation R grading system (0R = 0, 1R = 1, 2R = 2, 3R = 3) and any rejection score (ARS; calculated as 0R = 0, 1R = 1, 2R = 1; 3R = 1, or the number of rejections of any grade) were normalized for the total number of biopsy specimens. CAV was defined as coronary stenosis of 40% or more and/or distal pruning of secondary side branches. Thirty-two patients had undergone 3-dimensional intravascular ultrasound (IVUS) at baseline and with virtual histology (VH) IVUS at 24 months. RESULTS In univariate analysis, 6-month TRS (hazard ratio [HR], 1.9; 95% confidence interval [CI], 0.99-3.90, p = 0.05) and ARS (HR, 2.22; 95% CI, 1.01-4.95; p = 0.047) were associated with increased risk of CAV. In multivariate analysis, 6-month TRS (HR, 2.84; 95% CI, 1.44-6.91, p = 0.02) was significantly associated with increased risk of CAV onset. The 12- and 24-month rejection scores were not risk factors for the onset of CAV. By Kaplan-Meier analysis, 6-month TRS exceeding 0.3 was associated with a significantly shorter time to CAV onset (p = 0.018). There was direct correlation (r = 0.44, p = 0.012) between TRS at 6 months and the percentage of necrotic core demonstrated by VH-IVUS at 24 months. CONCLUSION Recurrent cellular rejection has a cumulative effect on the onset of CAV. The mechanism may be due to increased inflammation resulting in increased plaque burden suggesting a relationship between the immune basis of cellular rejection and CAV.

Sirolimus as Primary Immunosuppression Attenuates Allograft Vasculopathy With Improved Late Survival and Decreased Cardiac Events After Cardiac Transplantation

Background— We retrospectively analyzed the potential of sirolimus as a primary immunosuppressant in the long-term attenuation of cardiac allograft vasculopathy progression and the effects on cardiac-related morbidity and mortality. Methods and Results— Forty-five cardiac transplant recipients were converted to sirolimus 1.2 years (0.2, 4.0) after transplantation with complete calcineurin inhibitor withdrawal. Fifty-eight control subjects 2.0 years (0.2, 6.5 years) from transplantation were maintained on calcineurin inhibitors. Age, sex, ejection fraction, and time from transplantation to baseline intravascular ultrasound study were not different (P>0.2 for all) between the groups; neither were secondary immunosuppressants and use of steroids. Three-dimensional intravascular ultrasound studies were performed at baseline and 3.1 years (1.3, 4.6 years) later. Plaque index progression (plaque volume/vessel volume) was attenuated in the sirolimus group (0.7±10.5% versus 9.3±10.8%; P=0.0003) owing to reduced plaque volume in patients converted to sirolimus early (<2 years) after transplantation (P=0.05) and improved positive vascular remodeling (P=0.01) in patients analyzed late (>2 years) after transplantation. Outcome analysis in 160 consecutive patients maintained on 1 therapy was performed regardless of performance of intravascular ultrasound examinations. Five-year survival was improved with sirolimus (97.4±1.8% versus 81.8±4.9%; P=0.006), as was freedom from cardiac-related events (93.6±3.2% versus 76.9±5.5%; P=0.002). Conclusions— Substituting calcineurin inhibitor with sirolimus as primary immunosuppressant attenuates long-term cardiac allograft vasculopathy progression and may improve long-term allograft survival owing to favorable coronary remodeling. Because of the lack of randomization and retrospective nature of our analysis, the differences in outcome should be interpreted cautiously, and prospective clinical trials are required.

Echocardiographic Variables After Left Ventricular Assist Device Implantation 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.

Angiotensin converting enzyme inhibition modulates endogenous endothelin in chronic canine thoracic inferior vena caval constriction.

Endothelin (ET) is a potent vasoconstrictor peptide which is elevated in plasma in congestive heart failure. Recent studies suggest an important role for angiotensin II (AII) in the activation of ET in cultured cardiomyocytes. Chronic thoracic inferior vena caval constriction (TIVCC) is a model of reduced cardiac output that mimics the neurohumoral activation observed in congestive heart failure. We hypothesized that activation of the renin-angiotensin system in TIVCC plays a role in the activation of ET and that the elevation of endogenous ET contributes to the systemic and renal vasoconstriction that characterizes this model of venous congestion. We studied conscious dogs after 7 d of TIVCC in the presence or absence of chronic angiotensin converting enzyme inhibition with enalapril. TIVCC resulted in marked activation of plasma AII and ET in plasma, right atrium, lung, and renal medulla which was further localized to cardiomyocytes, pulmonary, and renal epithelial cells. Chronic angiotensin converting enzyme inhibition abolished the increases in plasma AII and ET during TIVCC. Acute endothelin A receptor blockade with FR-139317 resulted in significant decreases in mean arterial pressure and systemic vascular resistance in TIVCC. We conclude that activation of the renin-angiotensin system contributes to the activation of circulating and local ET in TIVCC and that this activation plays an important role in the regulation of arterial pressure and systemic vascular resistance in this model of congestive failure.

Replacement of calcineurin-inhibitors with sirolimus as primary immunosuppression in stable cardiac transplant recipients

Background. Calcineurin-inhibitor (CNI) nephrotoxicity is a major cause of morbidity and mortality after cardiac transplantation. The aim of this study was to assess over 2 years the safety and effect on renal function of withdrawal of CNI immunosuppression and replacement with sirolimus (SRL) in stable cardiac transplant recipients. Methods. CNI was substituted with SRL in 78 cardiac transplant recipients (SRL group) of whom 58 (group A) had CNI-induced renal impairment (glomerular filtration rate [GFR] <50 mL/min) and 20 (group B) had preserved renal function (GFR >50 mL/min). Fifty-one patients (CNI group) with renal impairment (GFR ≤50 mL/min) maintained on CNI served as controls. Secondary immunosuppressants were unchanged. Results. In the SRL group, GFR increased from 47.0±18.0 to 61.2±22.2 ml/min (P=0.0001) 24 months after SRL initiation. In Group A, GFR increased from 40.5±12.7 to 53.9±19.8 mL/min (P<0.0001). In Group B, GFR increased marginally from 67.2±15.8 to 83.5±27.8 mL/min (P=0.10). In the CNI group, GFR declined from 40.5±14.0 mL/min to 36.4±12.5 mL/min (P=0.23) after 24 months of follow up. There was no significant difference in cardiac rejection or cardiac allograft function. In SRL group, proteinuria increased from 299±622 mg/day to 517±795 mg/day (P=0.0002) 12 months after SRL initiation and then stabilized; it did not differ from CNI group at 24 months (637±806 vs. 514±744 mg/day, P=0.39). Uric acid decreased from 7.6±2.4 to 6.2±1.9 mg/dL (P=0.0007) in the SRL group. Conclusions. Graduated substitution of CNI with SRL in cardiac transplant recipients is safe and improves renal function, without cardiac compromise.