George L. Zorn

Transcatheter aortic-valve replacement with a self-expanding prosthesis.

BACKGROUND We compared transcatheter aortic-valve replacement (TAVR), using a self-expanding transcatheter aortic-valve bioprosthesis, with surgical aortic-valve replacement in patients with severe aortic stenosis and an increased risk of death during surgery. METHODS We recruited patients with severe aortic stenosis who were at increased surgical risk as determined by the heart team at each study center. Risk assessment included the Society of Thoracic Surgeons Predictor Risk of Mortality estimate and consideration of other key risk factors. Eligible patients were randomly assigned in a 1:1 ratio to TAVR with the self-expanding transcatheter valve (TAVR group) or to surgical aortic-valve replacement (surgical group). The primary end point was the rate of death from any cause at 1 year, evaluated with the use of both noninferiority and superiority testing. RESULTS A total of 795 patients underwent randomization at 45 centers in the United States. In the as-treated analysis, the rate of death from any cause at 1 year was significantly lower in the TAVR group than in the surgical group (14.2% vs. 19.1%), with an absolute reduction in risk of 4.9 percentage points (upper boundary of the 95% confidence interval, -0.4; P<0.001 for noninferiority; P = 0.04 for superiority). The results were similar in the intention-to-treat analysis. In a hierarchical testing procedure, TAVR was noninferior with respect to echocardiographic indexes of valve stenosis, functional status, and quality of life. Exploratory analyses suggested a reduction in the rate of major adverse cardiovascular and cerebrovascular events and no increase in the risk of stroke. CONCLUSIONS In patients with severe aortic stenosis who are at increased surgical risk, TAVR with a self-expanding transcatheter aortic-valve bioprosthesis was associated with a significantly higher rate of survival at 1 year than surgical aortic-valve replacement. (Funded by Medtronic; U.S. CoreValve High Risk Study ClinicalTrials.gov number, NCT01240902.).

Replacement of the Ascending Aorta and Aortic Valve with a Composite Graft: Results in 86 Patients

We reviewed our entire experience with composite graft replacement of the ascending aorta and aortic valve during a 63 month interval ending in December, 1979. Anuloaortic ectasia was the most common indication for operation, followed by aortic dissection (acute and chronic). Hospital mortality was 5% and was related to the preoperative functional status and the duration of intraoperative myocardial ischemia. Reoperation on the ascending aorta for reasons other than postoperative hemorrhage was required in five of the 82 hospital survivors (6%). By actuarial analysis, 90% of hospital survivors were free of any reoperation on the ascending aorta or aortic valve three years postoperatively, and 93% were free of reoperation related specifically to the composite graft. Pseudoaneurysms at the coronary ostia or distal aortic anastomosis were observed in five of 16 patients having postoperative angiography. One of the five patients has required reoperation. Follow-up has averaged 23.5 months (range: 0.2–60 months). Three year actuarial survival for the 86 patients was 81%, for 44 patients with anuloaortic ectasia was 88%, and for 31 patients with aortic dissection was 83%. Composite graft replacement of the ascending aorta and aortic valve is a satisfactory alternative to supracoronary graft replacement and aortic valve replacement. It offers the advantage of excluding all aneurysmal tissue from the aortic anulus to the innominate artery, thereby eliminating the potential for later development of aneurysms of the sinuses of Valsalva, a known complication of the supracoronary technique. It is the method of choice for patients with anuloaortic ectasia and cephalad displacement of the coronary ostia. It is suitable for many patients with acute or chronic dissection and for patients with sinuses of Valsalva aneurysms following previous operations on the ascending aorta or aortic valve.

A positive donor gram stain does not predict outcome following lung transplantation

BACKGROUND Many potential lung donors are excluded on the basis of a positive donor gram stain (DGS). We examined the association between a positive DGS and the probability of post-operative recipient pneumonia in the first 30 days. METHODS Ninety lung transplants (80 with a non-septic pre-transplant diagnosis) from 60 consecutive donors were evaluated for post-operative pneumonia (defined as a compatible clinical syndrome with fever, leukocytosis, chest X-ray abnormalities or histologic evidence obtained by transbronchial biopsy). DGS, white blood cell quantity, CXR and PaO(2)/FIO(2) (P/F) ratio were compared with immediate and 24-hour P/F ratio, length of mechanical ventilation and incidence of pneumonia. All recipients received standard prophylactic anti-bacterial coverage. Patients not surviving 30 days (n = 3) were excluded from this study, but none had evidence of pneumonia either by bronchoalveolar lavage (BAL), transbronchial biopsy or autopsy. RESULTS Fourteen (16%) of our 87 recipients developed pneumonia in the first 30 days after transplant. Of the 43 patients with a positive DGS, 5 (12%) developed pneumonia, compared to 9 of 44 (20%) with a negative DGS (p = 0.26). The mean post-operative P/F ratio (315 +/- 47 with a positive DGS, p = 0.3) and length of mechanical ventilation (2 days in each group) did not differ significantly between the negative and positive DGS groups. CONCLUSIONS In the current era of lung transplantation, DGS does not predict the development of early post-operative pneumonia and does not affect oxygenation or duration of mechanical ventilation; therefore, its role should be diminished when judging donor lung suitability.

Humoral Immunity to Vimentin Is Associated with Cardiac Allograft Injury in Nonhuman Primates

Immunity to autologous protein has not previously been described following nonhuman primate cardiac transplant. Native hearts and cardiac allografts from cynomolgus monkeys were assessed by immunohistology for vimentin, a highly conserved intermediate filament protein. IgM and IgG to vimentin were measured in serial sera from untreated (n = 4) or cyclosporine (CsA)‐treated (n = 8, 2 with ATG) cardiac allograft recipients, and in groups treated with anti‐CD154 antibody with (n = 6) or without ATG (n = 28). IgM or IgG reactive with vimentin was elaborated within 30 days with unmodified acute rejection (3/4) or in CsA‐treated animals (5/6). CD154 blockade did not prevent anti‐vimentin IgM (14/28) but tended to delay the IgG response during therapy (anti‐CD154: 8/28, p = 0.10 vs. CsA; anti‐CD154+ATG: 2/6). CAV and alloantibody were seen in 25 of 26 animals with grafts surviving over 30 days, including seven animals without increasing anti‐vimentin antibody. Anti‐vimentin antibodies and vascular complement deposition were found in rejected hearts. Acute and chronic alloimmunity disrupt modulation of autoreactivity to vimentin through pathways, which are resistant to CsA, but may be partially regulated by CD154.

Health Status After Transcatheter or Surgical Aortic Valve Replacement in Patients With Severe Aortic Stenosis at Increased Surgical Risk: Results From the CoreValve US Pivotal Trial.

OBJECTIVES This study sought to compare the health status outcomes for patients treated with either self-expanding transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (AVR). BACKGROUND In patients at increased surgical risk, TAVR with a self-expanding bioprosthesis is associated with improved 1-year survival compared with AVR. However, elderly patients may be just as concerned with quality-of-life improvement as with prolonged survival as a goal of treatment. METHODS Between 2011 and 2012, 795 patients with severe aortic stenosis at increased surgical risk were randomized to TAVR or AVR in the CoreValve US Pivotal Trial. Health status was assessed at baseline, 1 month, 6 months, and 1 year using the Kansas City Cardiomyopathy Questionnaire, Medical Outcomes Study Short-Form 12 Questionnaire, and EuroQOL 5-dimension questionnaire; growth curve models were used to examine changes over time. RESULTS Over the 1-year follow-up period, disease-specific and generic health status improved substantially for both treatment groups. At 1 month, there was a significant interaction between the benefit of TAVR over AVR and access site. Among surviving patients eligible for iliofemoral (IF) access, there was a clinically relevant early benefit with TAVR across all disease-specific and generic health status measures. Among the non-IF cohort, however, most health status measures were similar for TAVR and AVR, although there was a trend toward early benefit with TAVR on the Short-Form 12 Questionnaires physical health scale. There were no consistent differences in health status between TAVR and AVR at the later time points. CONCLUSIONS Health status improved substantially in surviving patients with increased surgical risk who were treated with either self-expanding TAVR or AVR. TAVR via the IF route was associated with better early health status compared with AVR, but there was no early health status benefit with non-IF TAVR compared with AVR. (Safety and Efficacy Study of the Medtronic CoreValve® System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902).

Combination Prophylaxis with Ganciclovir and Cytomegalovirus (CMV) Immune Globulin After Lung Transplantation: Effective CMV Prevention Following Daclizumab Induction

Despite the serious direct and indirect deleterious effects caused by cytomegalovirus (CMV), the optimal prophylactic strategy remains unknown. We sought to determine whether combination prophylaxis using intravenous ganciclovir (GCV) and CMV‐IVIG reduced the incidence of CMV compared to GCV alone. Donor CMV positive/recipient negative (D+/R–) patients received GCV (6 weeks i.v. + 6 weeks oral) and CMV‐IVIG (every 2 weeks for 7 doses), while R+ patients received GCV (2 weeks i.v. + 4 weeks oral) and CMV‐IVIG (every 2 weeks for 3 doses). The group receiving combination prophylaxis (GpA) was compared to a historical, case‐controlled group receiving GCV alone (GpB). Groups were matched by CMV donor/recipient serology, pretransplant diagnosis, age, and sex in reverse chronological order. Cyclosporine, azathioprine, and prednisone were used in both groups. Additionally, GpA received daclizumab induction therapy. Groups were compared as to the incidence of CMV disease, CMV infection, and acute rejection (AR). In GpA, 38 patients were evaluable and matched to 48 patients in GpB. Three GpA patients (8%) (2 D+/R–) developed CMV disease vs. 16 patients (33%) in GpB, p = 0.0077, Fishers exact. There was also a trend toward a delay in CMV onset (148 days in GpA vs. 92 days in GpB, p = 0.07, Mann–Whitney). CMV infection did not occur in GpA, and one case occurred in GpB. There was no difference in the incidence of AR (66% in GpA vs. 79% in GpB, p = 0.22, Fishers exact) or the need for cytolytic therapy between groups. Despite the use of daclizumab induction therapy, combination prophylaxis with GCV and CMV‐IVIG reduced the incidence and probably delayed the onset of CMV infection compared to GCV alone. Longer follow‐up will be needed to evaluate the impact of combination therapy on the incidence of bronchiolitis obliterans syndrome (BOS).

Prosthesis–patient mismatch in high-risk patients with severe aortic stenosis: A randomized trial of a self-expanding prosthesis

OBJECTIVES We compared the incidence of prosthesis-patient mismatch (PPM) between transcatheter aortic valve replacement (TAVR) using a self-expanding bioprosthesis and surgical aortic valve replacement (SAVR) in the CoreValve US High Risk Pivotal Trial. We sought to determine the influence of PPM on clinical outcomes. METHODS Patients with severe aortic stenosis and at increased risk for surgery were randomized 1:1 to TAVR or SAVR. Postoperative PPM was defined by the effective orifice area index (EOAi) as severe PPM (EOAi ≤ 0.65 cm(2)/m(2)) and no severe PPM (EOAi > 0.65 cm(2)/m(2)); clinical outcomes were analyzed in the TAVR arm (n = 389) and SAVR arm (n = 353). Left ventricular mass index and regression were analyzed at baseline and 1 year. RESULTS The incidence of severe PPM in the SAVR group at 1 year was 25.7% versus 6.2% in the TAVR group (P < .0001). Left ventricular mass index regression at 1 year was 6.8% for TAVR and 15.1% for SAVR in patients with severe PPM. At 1 year the rate of all-cause mortality and acute kidney injury were significantly greater in all patients (TAVR + SAVR) with severe PPM compared with no severe PPM (20.6% vs 12.0% [P = .0145] for death and 19.2% vs 8.5% [P = .0008] for acute kidney injury). CONCLUSIONS In patients with high surgical risk and severe aortic stenosis, severe PPM is more common in patients treated with SAVR than those treated with TAVR. Patients with severe PPM are a greater risk for death and acute kidney injury than patients without severe PPM.

Alloimmunity in Primate Heart Recipients with Cd154 Blockade: Evidence for Alternative Costimulation Mechanisms

Background. CD154 mediates key facets of humoral and cellular immunity to alloantigens, and is tolerogenic to influenza antigens in primates. Barriers to CD154-based tolerance induction for primate cardiac allografts have not previously been defined. Methods. Heterotopic cardiac allograft outcomes in cynomolgus monkeys treated with a CD154 inhibitor, IDEC-131 (n=27), were compared to no treatment (n=4) or cyclosporine A (n=6). Results. CD154 blockade significantly prolonged median allograft survival, from 6.2 (range 6, 7, n=4) days in untreated controls, to 39 (8,112, n=16) days with intensive monotherapy and 93 (>25, 386; n=3) days with added antithymocyte globulin (ATG), but did not yield tolerance. Alloantibody production was delayed but not prevented by IDEC-131 alone or with ATG, and was exacerbated by infusion of donor bone marrow (n=8). Expression of ICOS was prominent in graft infiltrating lymphocytes, and preceded elaboration of antidonor antibody and vasculopathy. Conclusion. CD154 monotherapy modulates primate cardiac alloimmunity, but does not readily induce tolerance. Targeting alternative costimulation pathways, including ICOS, may facilitate tolerance induction based on CD154 blockade.

Self-expanding transcatheter aortic valve replacement using alternative access sites in symptomatic patients with severe aortic stenosis deemed extreme risk of surgery

OBJECTIVES The CoreValve Extreme Risk US Pivotal Trial enrolled patients with symptomatic severe aortic stenosis deemed unsuitable for surgical aortic valve replacement. Implants were attempted using transfemoral access (n = 489) or an alternative access (n = 150). In present analysis, we sought to examine the safety and efficacy of CoreValve transcatheter aortic valve replacement using alternative access. METHODS The present study included 150 patients with prohibitive iliofemoral anatomy who were treated with the CoreValve transcatheter heart valve delivered by way of the subclavian artery (n = 70) or a direct aortic approach (n = 80). The echocardiograms were read by an independent core laboratory. The primary endpoint was all-cause mortality or major stroke at 12 months. RESULTS The preoperative aortic valve area was 0.72 ± 0.27 cm(2) and mean aortic valve gradient was 49.5 ± 17.0 mm Hg. After the transcatheter aortic valve replacement, the effective aortic valve area was 1.82 ± 0.64 cm(2) at 1 month and 1.85 ± 0.51 cm(2) at 12 months. The mean aortic valve gradient was 9.7 ± 5.8 mm Hg at 30 days and 9.5 ± 5.7 mm Hg at 12 months. The death or major stroke rate was 15.3% at 30 days and 39.4% at 12 months. The individual rate of all-cause mortality and major stroke was 11.3% and 7.5% at 30 days and 36.0% and 9.1% at 12 months. CONCLUSIONS These data demonstrate that the CoreValve transcatheter heart valve delivered by an alternative access provides a suitable alternative for treatment of extreme risk patients with symptomatic severe aortic stenosis, who have prohibitive iliofemoral anatomy and no surgical options.

Hyperacute lung rejection in the pig-to-human model. 2. Synergy between soluble and membrane complement inhibition

Azimzadeh A, Zorn GL III, Blair KSA, Zhang JP, Pfeiffer S, Harrison RA, Cozzi E, White DJG, Pierson RN III. Hyperacute lung rejection in the pig‐to‐human model. 2. Synergy between soluble and membrane complement inhibition. Xenotransplantation 2003; 10: 120–131.