John B. O'Connell

Original InvestigationRisk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients: Results From the ROADMAP Study

BACKGROUNDnData for left ventricular assist devices (LVADs) in patients with noninotrope-dependent heart failure (HF) are limited.nnnOBJECTIVESnThe goal of this study was to evaluate HeartMate II (HMII) LVAD support versus optimal medical management (OMM) in ambulatory New York Heart Association functional class IIIB/IV patients meeting indications for LVAD destination therapy but not dependent on intravenous inotropic support.nnnMETHODSnThis was a prospective, multicenter (Nxa0= 41), observational study of 200 patients (97 LVAD, 103 OMM). Entry criteria includedxa0≥1 hospitalization for HF in the last 12 months and 6-min walk distance (6MWD)xa0<300 m. The primary composite endpoint was survival on original therapy with improvement in 6MWDxa0≥75 m at 12 months.nnnRESULTSnLVAD patients were more severely ill, with more patients classified as Interagency Registry for Mechanically Assisted Circulatory Support profile 4 (65% LVAD vs. 34% OMM; pxa0< 0.001) than 5 to 7. More LVAD patients met the primary endpoint (39% LVAD vs. 21% OMM; odds ratio: 2.4 [95% confidence interval: 1.2 to 4.8]; pxa0= 0.012). On the basis of as-treated analysis, 12-month survival was greater for LVAD versus OMM (80 ± 4% vs. 63 ± 5%; pxa0= 0.022) patients. Adverse events were higher in LVAD patients, at 1.89 events/patient-year (EPPY), primarily driven by bleeding (1.22 EPPY), than with OMM, at 0.83 EPPY, primarily driven by worsening HF (0.68 EPPY). Most patients (80% LVAD vs. 62% OMM; pxa0< 0.001) required hospitalizations. Health-related quality of life (HRQol) and depression improved from baseline more significantly with LVADs than with OMM (Δ visual analog scale: 29 ± 25 vs. 10 ± 22 [pxa0< 0.001]; Δ Patient Health Questionnaire-9: -5 ± 7 vs. -1 ± 5 [pxa0< 0.001]).nnnCONCLUSIONSnSurvival with improved functional status was better with HMII LVAD compared with OMM. Despite experiencing more frequent adverse events, LVAD patients improved more in HRQol and depression. The results support HMII use in functionally limited, noninotrope-dependent HF patients with poor HRQoL. (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device [LVAD] and Medical Management [ROADMAP]; NCT01452802).

Myocarditis and idiopathic dilated cardiomyopathy

n Abstractn n Idiopathic dilated cardiomyopathy (IDC) accounts for 25% of cases of heart failure in the United States. Understanding the relationship between an inciting event or agent and the development of IDC has progressed only recently. Once IDC has developed, treatment is palliative and little can be done to alter the natural course of the disease. Active myocarditis, a suspected precursor of IDC, is myocardial inflammation and injury without ischemia. The disease ranges from a self-limited flulike illness to one of serious consequence with arrhythmias, heart failure, or death. Many agents have been associated with myocarditis, and the clinical manifestations depend on an interplay between the inciting agent and the host response. The development of a murine model and the expanded use of endomyocardial biopsy using the Dallas criteria have increased our understanding of myocarditis and its sequelae. Therapy consists of managing symptoms using conventional medical regimens for heart failure. Immunosuppressive therapy should be reserved for patients with biopsy-proven disease who have failed conventional therapy. Continued deterioration warrants ventricular assistance and consideration of cardiac transplantation.n n

OUTCOME OF CARDIAC TRANSPLANT RECIPIENTS WITH A POSITIVE DONOR-SPECIFIC CROSSMATCH—PRELIMINARY RESULTS WITH PLASMAPHERESIS

To assess the influence of a positive T or B cell IgG crossmatch on the development of rejection and mortality following cardiac transplantation, we reviewed all cardiac transplants performed in Utah between March 1985 and October 1990. Of the 328 cardiac allograft recipients, 11 (3.4%) had an IgG positive crossmatch. Actuarial survival at 24 months in the positive crossmatch group was 57.3% +/- 0.02 while that of the controls was 86.1% +/- 2.1 (P < 0.05). Allograft rejection occurred earlier in recipients with a positive crossmatch (10.0 +/- 5.8 days versus 34.0 +/- 2.3 days, P < 0.001). The first allograft rejection episode in patients with a positive crossmatch was characterized by immunoglobulin and complement deposition in small blood vessels and interstitial edema and endothelial cell activation in the absence of a lymphocytic infiltrate. Furthermore, the allograft rejection in the positive crossmatch group was accompanied by hemodynamic compromise in a large proportion of the patients (73%). In addition to augmentation of immunosuppression, plasma exchange therapy was performed within the first week following transplantation in 8 of the 11 positive crossmatch patients. Survival in the patients treated with plasma exchange (75%) appears to be better than in those not receiving plasma exchange (33%) within one week of transplantation. While immunosuppressive therapy aimed at the humoral arm of the immune system and plasma exchange therapy may improve survival in recipients with a positive donor-specific crossmatch, survival is worse in patients with a positive crossmatch than in patients with a negative crossmatch. Thus, it would appear prudent to prospectively crossmatch cardiac transplant candidates with a greater risk of developing a positive crossmatch, such as those potential recipients with an elevated level of panel-reactive antibodies.

Role of beta-adrenergic receptor downregulation in the peak exercise response in patients with heart failure due to idiopathic dilated cardiomyopathy

The effect of beta-adrenergic receptor downregulation on peak exercise response in patients with heart failure has not been directly investigated. Seventy-two patients with idiopathic dilated cardiomyopathy who had a mean ejection fraction of 23 +/- 1% (mean +/- SEM) and New York Heart Association class II or III symptoms were investigated. Subjects underwent maximal exercise testing on a bicycle or a treadmill, hemodynamic assessment by right heart catheterization, and measurement of total beta-adrenergic receptor density by 125I-iodocyanopindolol binding performed in the right ventricular endomyocardial biopsy tissue and in peripheral lymphocytes. Endomyocardial biopsy beta-adrenergic receptor density (Bmax) was markedly decreased (45 +/- 2 fmol/mg), and significantly lower than lymphocytes Bmax (107 +/- 14 fmol/mg; p < 0.05). By univariate analysis, all exercise variables correlated significantly with biopsy tissue Bmax but not with lymphocyte Bmax. Maximal exercise oxygen consumption (VO2max) yielded the highest correlation with Bmax (r2 = 0.61, p < 0.001). By stepwise regression analysis, VO2 max, delta heart rate x systolic blood pressure, and ejection fraction were all independently related to Bmax. Myocardial beta-adrenergic receptor downregulation is likely to be partially responsible for the reduced chronotropic and inotropic responses to peak exercise in patients with mild to moderate symptomatic heart failure due to idiopathic dilated cardiomyopathy.

Transient bundle branch block following use of hypothermic cardioplegia in coronary artery bypass surgery: High incidence without perioperative myocardial infarction

Hypothermic cardioplegia (HCP) is a method commonly used for myocardial preservation at the time of aortic cross-clamping during coronary artery bypass grafting (CABG). This study assessed the frequency and significance of transient bundle branch block (BBB) in 50 patients undergoing CABG using HCP compared to 61 controls. All patients had normal QRS complexes on preoperative ECG. CLinical, hemodynamic, and operative data were similar in both groups. Seventeen (34%) of the HCP group and four (6%) of the controls developed postoperative BBB (p less than 0.001). These changes were transient in all but three patients in the HCP group. None of the HCP patients with transient BBB had evidence of perioperative myocardial infarction. Clinical and operative parameters did not provide prediction of development of transient BBB. This study demonstrates that transient BBB in the immediate post-CABG period occurs commonly with the use of HCP and does not indicate myocardial necrosis.

Detection of allograft endothelial cells of recipient origin following ABO-compatible, nonidentical cardiac transplantation.

Endothelial cells serve an important role in augmenting immune responses through enhanced expression of MHC class II antigens. Immune-mediated vascular injury associated with rejection requires reendothelialization to restore vascular integrity. The origin of the reparative endothelial cells can be determined when ABO antigens expressed on these cells differ in the donor and recipient. To assess the frequency and significance of reendothelialization by recipient endothelial cells, we stained serial endomyocardial biopsies for ABO antigens in 34 (13%) compatible, nonidentical cardiac allograft recipients of 268 cardiac transplant procedures. In ten (30%) the allograft endothelial cells expressed the characteristics of the recipient (five partial and five complete) within 7.5 +/- 1.0 months (mean +/- SEM) after transplantation. Over 26.3 +/- 2.5 months follow-up no differences could be detected in pretransplant characteristics, allograft survival, survivor rejection morbidity, long-term allograft function, and presence of coronary vasculopathy between those whose endothelial cells expressed recipient blood group antigens and those who did not, which may merely be a reflection of the small sample size. This study indicates that recipient reendothelialization occurs frequently following cardiac transplantation and may result from immune-mediated vascular injury. The effect of recipient reendothelialization on allograft tolerance requires further investigation.

Clinical and pathologic findings of myocarditis in two families with dilated cardiomyopathy

The use of endomyocardial biopsy and gallium-67 scans in patients with dilated cardiomyopathy (DCM) has demonstrated the presence of myocardial inflammation in a subset of patients. A family with DCM was studied with endomyocardial biopsy and gallium-67 scanning; both identified the presence of myocarditis in the proband. Evaluation of histologic sections from decreased family members revealed myocarditis as the principal pathologic finding. This patient identified during life demonstrated a defect in suppressor lymphocytic function and improved with immunosuppressive therapy. A second family with DCM was discovered when postmortem examination of the proband and his fathers heart showed myocarditis. A living sibling was identified with asymptomatic myocardial dysfunction. Longitudinal follow-up of surviving members of both families are in progress. This study indicates that thorough diagnostic evaluation of all patients with familial DCM should be pursued to identify subgroups with potentially treatable inflammation.

Task force 1: Organization of heart transplantation in the U.S.

Until recently, tr~ns~l~~~~tion nnd organ ~r~~~ure~~~~nt cfforts in the United States of America were pearly orguniaed. Uniform A~~t~rn~~~l Gift Act of 1 form~li%ed a ensus definition of brain de~rh and paved the way for d~n~~t~on of solid organs ( IL Actual organ ~ro~urem~~t and d~st~but~on, however, remained 1 ely the r~s~onsibil~ ity of i~ividu~~ tnnspiant centers a informal consortia until the early 1980s. Computer systems, such as those by the North American Transplnnt Coordinators ion (NATCB), the Southcsstern Organ Prc)curernent Foundation (SE6PF) and the Southwest Organ Bank #+KIB), facilitated the regional ~ro~ur~rne~~t and distribution of organs, These voluntary regional ~~rn~uteri~~d networks were initially adequate but evenruatty proved inuufficient to meet the national need spurred by ~rn~r~~ven~~nts in -+?rm reservation when hearts could be preserved for h h and long distance p~~~~~rn~nt hrcnme a reality.

Gallium-67 Imaging in Cardiomyopathy

Myocardial gallium-67 imaging may be valuable in the diagnosis of inflammatory lesions of the heart. Myocardial gallium-67 localization in 3 patients with suspect inflammatory disease was described. (RJC)

Coxsackie viral myocarditis

Coxsackie viral myocarditis is a common disease, yet idiopathic dilated cardiomyopathy is a less common consequence. Insights gained from studying the Coxsackie virus B-3 murine model of myocarditis has led to the hypothesis that an acute Coxsackie viral myocarditis can result in persistent, non-viral mediated cellular responses that result in a chronic inflammatory state leading to progressive myocyte loss and ultimate development of dilated cardiomyopathy. Although the evidence linking myocarditis to dilated cardiomyopathy is circumstantial in man, the identification of defects in immunoregulation may provide the impetus to further research into the pathogenesis and ultimately the development of more rational therapies directed at modulating immune responses to alter the natural history of clinical dilated cardiomyopathy.