Alan Gass

Controlled Trial of Intravenous Immune Globulin in Recent-Onset Dilated Cardiomyopathy

BackgroundThis prospective placebo-controlled trial was designed to determine whether intravenous immune globulin (IVIG) improves left ventricular ejection fraction (LVEF) in adults with recent onset of idiopathic dilated cardiomyopathy or myocarditis. Methods and ResultsSixty-two patients (37 men, 25 women; mean age ±SD 43.0±12.3 years) with recent onset (≤6 months of symptoms) of dilated cardiomyopathy and LVEF ≤0.40 were randomized to 2 g/kg IVIG or placebo. All underwent an endomyocardial biopsy before randomization, which revealed cellular inflammation in 16%. The primary outcome was change in LVEF at 6 and 12 months after randomization. Overall, LVEF improved from 0.25±0.08 to 0.41±0.17 at 6 months (P <0.001) and 0.42±0.14 (P <0.001 versus baseline) at 12 months. The increase was virtually identical in patients receiving IVIG and those given placebo (6 months: IVIG 0.14±0.12, placebo 0.14±0.14; 12 months: IVIG 0.16±0.12, placebo 0.15±0.16). Overall, 31 (56%) of 55 patients at 1 year had an increase in LVEF ≥0.10 from study entry, and 20 (36%) of 56 normalized their ejection fraction (≥0.50). The transplant-free survival rate was 92% at 1 year and 88% at 2 years. ConclusionsThese results suggest that for patients with recent-onset dilated cardiomyopathy, IVIG does not augment the improvement in LVEF. However, in this overall cohort, LVEF improved significantly during follow-up, and the short-term prognosis remains favorable.

A Phase 1/2 Clinical Trial of Enzyme Replacement in Fabry Disease: Pharmacokinetic, Substrate Clearance, and Safety Studies

Fabry disease results from deficient alpha-galactosidase A (alpha-Gal A) activity and the pathologic accumulation of the globotriaosylceramide (GL-3) and related glycosphingolipids, primarily in vascular endothelial lysosomes. Treatment is currently palliative, and affected patients generally die in their 40s or 50s. Preclinical studies of recombinant human alpha-Gal A (r-halphaGalA) infusions in knockout mice demonstrated reduction of GL-3 in tissues and plasma, providing rationale for a phase 1/2 clinical trial. Here, we report a single-center, open-label, dose-ranging study of r-halphaGalA treatment in 15 patients, each of whom received five infusions at one of five dose regimens. Intravenously administered r-halphaGalA was cleared from the circulation in a dose-dependent manner, via both saturable and non-saturable pathways. Rapid and marked reductions in plasma and tissue GL-3 were observed biochemically, histologically, and/or ultrastructurally. Clearance of plasma GL-3 was dose-dependent. In patients with pre- and posttreatment biopsies, mean GL-3 content decreased 84% in liver (n=13), was markedly reduced in kidney in four of five patients, and after five doses was modestly lowered in the endomyocardium of four of seven patients. GL-3 deposits were cleared to near normal or were markedly reduced in the vascular endothelium of liver, skin, heart, and kidney, on the basis of light- and electron-microscopic evaluation. In addition, patients reported less pain, increased ability to sweat, and improved quality-of-life measures. Infusions were well tolerated; four patients experienced mild-to-moderate reactions, suggestive of hypersensitivity, that were managed conservatively. Of 15 patients, 8 (53%) developed IgG antibodies to r-halphaGalA; however, the antibodies were not neutralizing, as indicated by unchanged pharmacokinetic values for infusions 1 and 5. This study provides the basis for a phase 3 trial of enzyme-replacement therapy for Fabry disease.

Peripheral Extracorporeal Membrane Oxygenation: Comprehensive Therapy for High-Risk Massive Pulmonary Embolism

BACKGROUND Although commonly reserved as a last line of defense, experienced centers have reported excellent results with pulmonary embolectomy for massive and submassive pulmonary embolism (PE). We present a contemporary surgical series for PE that demonstrates the utility of peripheral extracorporeal membrane oxygenation (pECMO) for high-risk surgical candidates. METHODS Between June 2005 and April 2011, 29 patients were treated for massive or submassive pulmonary embolism, with surgical embolectomy performed in 26. Four high-risk patients were placed on pECMO, established by percutaneously cannulating the right atrium through a femoral vein and perfusing by a Dacron graft anastomosed to the axillary artery. A small, extracorporeal, rotary assist device was used, interposing a compact oxygenator in the circuit, and maintaining anticoagulation with heparin. RESULTS Extracorporeal membrane oxygenation was weaned in 3 of 4 patients after 5.3 days (5, 5, and 6), with normalization of right ventricular dysfunction and pulmonary artery pressure (44.0 ± 2.0 to 24.5 ± 5.5 mm Hg) by ECHO. Follow-up computed tomographies showed several peripheral, nearly resorbed emboli in 1 case and complete resolution in 2 others. The fourth patient, not improving after 10 days, underwent surgery where an embolic liposarcoma was extracted. For all 29 cases, hospital and 30-day mortality was 0% and all patients were discharged, with average postoperative length of stay of 15 days for embolectomy and 17 days for pECMO. CONCLUSIONS Heparin therapy with pECMO support is a rapid, effective option for patients who might benefit from pulmonary embolectomy but are at high risk for surgery.

Temporal Trends in Incidence and Outcomes of Peripartum Cardiomyopathy in the United States: A Nationwide Population‐Based Study

Background The reported incidence of peripartum cardiomyopathy (PPCM) in the United States varies widely. Furthermore, limited information is available on the temporal trends in incidence and outcomes of PPCM. Methods and Results We queried the 2004‐2011 Nationwide Inpatient Sample databases to identify all women aged 15 to 54 years with the diagnosis of PPCM. Temporal trends in incidence (per 10 000 live births), maternal major adverse events (MAE; defined as in‐hospital mortality, cardiac arrest, heart transplant, mechanical circulatory support, acute pulmonary edema, thromboembolism, or implantable cardioverter defibrillator/permanent pacemaker implantation), cardiogenic shock, and mean length of stay were analyzed. From 2004 to 2011, we identified 34 219 women aged 15 to 54 years with PPCM. The overall PPCM rate was 10.3 per 10 000 (or 1 in 968) live births. PPCM incidence increased from 8.5 to 11.8 per 10 000 live births (Ptrend<0.001) over the past 8 years. MAE occurred in 13.5% of patients. There was no temporal change in MAE rate, except a small increase in in‐hospital mortality and mechanical circulatory support (Ptrend<0.05). Cardiogenic shock increased from 1.0% in 2004 to 4.0% in 2011 (Ptrend<0.001). Mean length of stay decreased during the study period. Conclusion From 2004 to 2011, the incidence of PPCM has increased in the United States. Maternal MAE rates overall have remained unchanged while cardiogenic shock, utilization of mechanical circulatory support, and in‐hospital mortality have increased during the study period. Further study of the mechanisms underlying these adverse trends in the incidence and outcomes of PPCM are warranted.

Tacrolimus monotherapy in adult cardiac transplant recipients: Intermediate-term results

BACKGROUND Tacrolimus (FK506) is a macrolide antibiotic that inhibits T-cell activation and proliferation. To date, all published trials have used tacrolimus and steroids in combination with either azathioprine or mycophenolate mofetil. Previous experience with pediatric cardiac transplant patients at our institution suggested that use of tacrolimus alone provides an adequate level of immunosuppression and that withdrawal of steroids is readily achieved in most recipients. Between January 1, 1996, and July 7, 1999, we performed 77 adult cardiac transplants. Forty-three of these patients received tacrolimus and prednisone as primary immunosuppression, without azathioprine or mycophenolate mofetil. Thirty-two of the 43 patients started on tacrolimus have been weaned off steroids and are maintained on monotherapy. These latter patients form the basis of this report. The mean time for achieving monotherapy was 246 +/- 127 days (range, 106 to 730). Grade > or = 2 rejection occurred at 0.40 episodes per patient in the first 90 days (a combination of Grades 2 and 3A/3B rejections). The freedom from treated rejection (includes all 3A/3B and Grade 2 rejection in the first 90 days) was 69% at 90 days and 52% at 1 year. One patient (of 32) had documented cytomegalovirus infection (gastritis) diagnosed at 8 months post-transplant. We observed 1 case of transplant vasculopathy and 1 case of post-transplant lymphoproliferative disorder during the follow-up period. Our results show that use of tacrolimus alone after steroid weaning provides effective immunosuppression with low incidence of rejection, cytomegalovirus infection, transplant arteriopathy, or post-transplant lymphoproliferative disease.

Recent improvements in outcome with the Novacor left ventricular assist device.

BACKGROUND The Novacor implantable, electrically powered, wearable, left ventricular assist device (LVAD) has been used as a bridge to transplantation at our institution since 1994. Recent changes in protocol have resulted in a decreased incidence of infections, thromboembolism, and mortality. METHODS We reviewed the medical records of all 43 patients who received implantable LVADs at the Mount Sinai Medical Center. After 1998, a number of protocol modifications were instituted. Vascular grafts were changed from a low-porosity, woven polyester (Cooley) to a gelatin-sealed, knitted polyester graft (Vascutek), the devices were implanted pre-peritoneally rather than in the posterior rectus sheath, and extensive drainage of the chest and pre-peritoneal pocket was used. The following anti-coagulation regimen was used: low-molecular-weight Dextran for 1 day, initiated after chest tube drainage <50 cc/hour; then IV heparin for 10 to 14 days, beginning at 500 U/hour, slowly increasing partial thromboplastin time to 1.5 to 2 x control; and finally Coumadin, maintaining the international normalized ratio at 2.5 to 3.5. Daily aspirin, 325 mg, was begun on post-operative Day 7. We compared 22 patients who electively underwent surgery before the changes, Group I, with 18 patients treated thereafter, Group II. RESULTS Groups I and II were well matched with regard to age (47 vs 44 years); cause of heart failure (idiopathic, 50% vs 44%; ischemic, 50% vs 56%), and duration of support (79 vs 76 days). The incidence of thromboembolic cerebrovascular events was significantly less in Group II (6%) than in Group I (23%), p = 0.025. The incidence of bleeding increased mildly in Group I. Pocket infections occurred in 27% of Group I patients vs 11% of Group II patients, p = 0.018. Only 2 patients (11%) in Group II died while receiving device support, vs 7 (32%) in Group I, p = 0.019. CONCLUSIONS Our results indicate that pre-peritoneal implantation, use of a new generation of vascular grafts, extensive drainage, and a more restricted anti-coagulation regimen improve outcome after Novacor LVAD implantation for advanced heart failure.

Calcineurin Inhibitor-Associated Early Renal Insufficiency in Cardiac Transplant Recipients Risk Factors and Strategies for Prevention and Treatment

Cardiac transplantation is the definitive treatment for eligible patients with end-stage cardiac failure. Techniques have evolved to reduce surgical mortality to under 5%. Immediate and subsequent long-term survival is more dependent on acute and chronic rejection and the complications of immunosuppressive therapy. Ten-year survival is greater than 50%.The success of transplantation over the last 20 years has been largely due to the advances in immunosuppression. The most notable and dramatic milestone was the introduction of cyclosporine in the early 1980s, which resulted in a significant improvement in allograft and patient survival. Cyclosporine is a peptide that inhibits the immune system by suppressing T-helper cell activation via inhibition of calcineurin, a critical intracellular enzyme. Tacrolimus has a similar (but not identical) mechanism of action, and was introduced in the 1990s. Drugs such as cyclosporine and tacrolimus, generically referred to as calcineurin inhibitors, have become the cornerstones of immunosuppressive protocols.As a group, calcineurin inhibitors have adverse effects, including neurotoxicity, hypertension, and nephrotoxicity, which complicate their use. Early renal insufficiency manifests as postoperative oliguria (<50 mL/h urine output) or rising serum creatinine levels. There are a variety of postulated causes for calcineurin inhibitor-associated early renal insufficiency including direct calcineurin inhibitor-mediated renal arteriolar vasoconstriction, increased levels of endothelin-1 (a potent vasoconstrictor), as well as decreased nitric oxide production and alterations in the kidney’s ability to adjust to changes in serum tonicity.Once early renal insufficiency occurs, no single treatment has been shown to be effective. Approaches discussed in this paper include reduction in calcineurin inhibitor dosages, as well as various drugs to promote increased renal perfusion such as misoprostol and dopamine. In addition, the paper emphasizes the importance of ruling out other causes of renal insufficiency in the early postoperative period, including volume depletion, depressed cardiac output, and mechanical obstruction to urine flow.Given that there is no highly efficacious treatment for this syndrome, ways to avoid its occurrence are desirable. One paper is referenced that suggests that avoidance of rapid changes in tacrolimus level during the first three days of therapy is associated with a low occurrence of early renal insufficiency.

A prospective, randomized trial of single-drug versus dual-drug immunosuppression in heart transplantation: the tacrolimus in combination, tacrolimus alone compared (TICTAC) trial.

Background— Cardiac transplantation, a procedure nearly abandoned in the 1970s, has evolved into the standard of care for appropriate patients with end-stage heart failure. Much of this success has been due to improvements in immunosuppression, including the introduction of a triple-drug regimen. Retrospective reports suggested that single-drug immunosuppression with tacrolimus was feasible. As such, a prospective, randomized trial was conducted to test this approach. Methods and Results— One hundred fifty adult de novo heart transplant recipients were enrolled in a prospective, randomized, controlled, open-label trial comparing tacrolimus monotherapy (MONO) with tacrolimus and mycophenolate mofetil therapy (COMBO). Corticosteroids were used in the early postoperative period but discontinued in all patients over 8 to 9 weeks. The primary end point was the composite biopsy score at 6 months after transplant. Patients were followed for 1 to 5 years. The composite biopsy score was similar between groups at 6 and 12 months: 6-month MONO, 0.70±0.44 (95% confidence interval, 0.60 to 0.80) versus COMBO, 0.65±0.40 (95% confidence interval, 0.55 to 0.74; P =0.44). Allograft vasculopathy was assessed by angiography and intravascular ultrasound, with no significant differences noted. Three-year survival was also similar (92.4% MONO versus 97% COMBO; P =0.58, log-rank). Conclusions— Addition of mycophenolate to single-agent immunosuppression did not provide an advantage over single-agent immunosuppression in terms of rejection, allograft vasculopathy, or 3-year survival. Corticosteroids, which have traditionally been a mainstay of therapy, were successfully discontinued in all patients. These conclusions are tempered by the limited statistical power associated with a sample size of only 150 patients. Clinical Trial Registration— URL: . Unique identifier: [NCT00299221][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00299221&atom=%2Fcirchf%2F4%2F2%2F129.atomBackground—Cardiac transplantation, a procedure nearly abandoned in the 1970s, has evolved into the standard of care for appropriate patients with end-stage heart failure. Much of this success has been due to improvements in immunosuppression, including the introduction of a triple-drug regimen. Retrospective reports suggested that single-drug immunosuppression with tacrolimus was feasible. As such, a prospective, randomized trial was conducted to test this approach. Methods and Results—One hundred fifty adult de novo heart transplant recipients were enrolled in a prospective, randomized, controlled, open-label trial comparing tacrolimus monotherapy (MONO) with tacrolimus and mycophenolate mofetil therapy (COMBO). Corticosteroids were used in the early postoperative period but discontinued in all patients over 8 to 9 weeks. The primary end point was the composite biopsy score at 6 months after transplant. Patients were followed for 1 to 5 years. The composite biopsy score was similar between groups at 6 and 12 months: 6-month MONO, 0.70±0.44 (95% confidence interval, 0.60 to 0.80) versus COMBO, 0.65±0.40 (95% confidence interval, 0.55 to 0.74; P=0.44). Allograft vasculopathy was assessed by angiography and intravascular ultrasound, with no significant differences noted. Three-year survival was also similar (92.4% MONO versus 97% COMBO; P=0.58, log-rank). Conclusions—Addition of mycophenolate to single-agent immunosuppression did not provide an advantage over single-agent immunosuppression in terms of rejection, allograft vasculopathy, or 3-year survival. Corticosteroids, which have traditionally been a mainstay of therapy, were successfully discontinued in all patients. These conclusions are tempered by the limited statistical power associated with a sample size of only 150 patients. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00299221.

Current practices: immunosuppression induction, maintenance, and rejection regimens in contemporary post-heart transplant patient treatment.

Cardiac transplantation is the definitive treatment for eligible patients with end-stage cardiomyopathy. Survival rates have improved dramatically during the last 10 years, especially since the advent of cyclosporine-A. Cardiac allograft rejection, previously considered a major cause of early mortality after transplantation, is no longer the limiting factor for early survival, with the use of newer and more specific immunosuppression regimens. Very few randomized, prospective trials, including comparisons between immunosuppression regimens, have been conducted in this area. Therefore, practices vary with physician and institutional experience. Most centers use a multipronged approach to immunosuppression, targeting multiple sites in the immune cascade that lead to allograft rejection. Multiple new agents in development are reviewed. Drugs such as sirolimus and its derivative, everolimus, act on specific intracellular receptors within lymphocytes, whereas other medications such as Daclizumab (Roche Laboratories, Nutley, NJ) block the interleukin-2 receptor on the surface of activated T cells. The immune response to foreign antigens is complex, with multiple redundant levels. Immunosuppression regimens continue to seek a fine balance between overimmunosuppression and insufficient protection, which may lead to allograft rejection or loss.

A Prospective, Randomized Trial of Single-Drug Versus Dual-Drug Immunosuppression in Heart TransplantationClinical Perspective

Background— Cardiac transplantation, a procedure nearly abandoned in the 1970s, has evolved into the standard of care for appropriate patients with end-stage heart failure. Much of this success has been due to improvements in immunosuppression, including the introduction of a triple-drug regimen. Retrospective reports suggested that single-drug immunosuppression with tacrolimus was feasible. As such, a prospective, randomized trial was conducted to test this approach. Methods and Results— One hundred fifty adult de novo heart transplant recipients were enrolled in a prospective, randomized, controlled, open-label trial comparing tacrolimus monotherapy (MONO) with tacrolimus and mycophenolate mofetil therapy (COMBO). Corticosteroids were used in the early postoperative period but discontinued in all patients over 8 to 9 weeks. The primary end point was the composite biopsy score at 6 months after transplant. Patients were followed for 1 to 5 years. The composite biopsy score was similar between groups at 6 and 12 months: 6-month MONO, 0.70±0.44 (95% confidence interval, 0.60 to 0.80) versus COMBO, 0.65±0.40 (95% confidence interval, 0.55 to 0.74; P =0.44). Allograft vasculopathy was assessed by angiography and intravascular ultrasound, with no significant differences noted. Three-year survival was also similar (92.4% MONO versus 97% COMBO; P =0.58, log-rank). Conclusions— Addition of mycophenolate to single-agent immunosuppression did not provide an advantage over single-agent immunosuppression in terms of rejection, allograft vasculopathy, or 3-year survival. Corticosteroids, which have traditionally been a mainstay of therapy, were successfully discontinued in all patients. These conclusions are tempered by the limited statistical power associated with a sample size of only 150 patients. Clinical Trial Registration— URL: . Unique identifier: [NCT00299221][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00299221&atom=%2Fcirchf%2F4%2F2%2F129.atomBackground—Cardiac transplantation, a procedure nearly abandoned in the 1970s, has evolved into the standard of care for appropriate patients with end-stage heart failure. Much of this success has been due to improvements in immunosuppression, including the introduction of a triple-drug regimen. Retrospective reports suggested that single-drug immunosuppression with tacrolimus was feasible. As such, a prospective, randomized trial was conducted to test this approach. Methods and Results—One hundred fifty adult de novo heart transplant recipients were enrolled in a prospective, randomized, controlled, open-label trial comparing tacrolimus monotherapy (MONO) with tacrolimus and mycophenolate mofetil therapy (COMBO). Corticosteroids were used in the early postoperative period but discontinued in all patients over 8 to 9 weeks. The primary end point was the composite biopsy score at 6 months after transplant. Patients were followed for 1 to 5 years. The composite biopsy score was similar between groups at 6 and 12 months: 6-month MONO, 0.70±0.44 (95% confidence interval, 0.60 to 0.80) versus COMBO, 0.65±0.40 (95% confidence interval, 0.55 to 0.74; P=0.44). Allograft vasculopathy was assessed by angiography and intravascular ultrasound, with no significant differences noted. Three-year survival was also similar (92.4% MONO versus 97% COMBO; P=0.58, log-rank). Conclusions—Addition of mycophenolate to single-agent immunosuppression did not provide an advantage over single-agent immunosuppression in terms of rejection, allograft vasculopathy, or 3-year survival. Corticosteroids, which have traditionally been a mainstay of therapy, were successfully discontinued in all patients. These conclusions are tempered by the limited statistical power associated with a sample size of only 150 patients. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00299221.