Thomas E. MacGillivray

Extended Mechanical Circulatory Support With a Continuous-Flow Rotary Left Ventricular Assist Device

OBJECTIVES This study sought to evaluate the use of a continuous-flow rotary left ventricular assist device (LVAD) as a bridge to heart transplantation. BACKGROUND LVAD therapy is an established treatment modality for patients with advanced heart failure. Pulsatile LVADs have limitations in design precluding their use for extended support. Continuous-flow rotary LVADs represent an innovative design with potential for small size and greater reliability by simplification of the pumping mechanism. METHODS In a prospective, multicenter study, 281 patients urgently listed (United Network of Organ Sharing status 1A or 1B) for heart transplantation underwent implantation of a continuous-flow LVAD. Survival and transplantation rates were assessed at 18 months. Patients were assessed for adverse events throughout the study and for quality of life, functional status, and organ function for 6 months. RESULTS Of 281 patients, 222 (79%) underwent transplantation, LVAD removal for cardiac recovery, or had ongoing LVAD support at 18-month follow-up. Actuarial survival on support was 72% (95% confidence interval: 65% to 79%) at 18 months. At 6 months, there were significant improvements in functional status and 6-min walk test (from 0% to 83% of patients in New York Heart Association functional class I or II and from 13% to 89% of patients completing a 6-min walk test) and in quality of life (mean values improved 41% with Minnesota Living With Heart Failure and 75% with Kansas City Cardiomyopathy questionnaires). Major adverse events included bleeding, stroke, right heart failure, and percutaneous lead infection. Pump thrombosis occurred in 4 patients. CONCLUSIONS A continuous-flow LVAD provides effective hemodynamic support for at least 18 months in patients awaiting transplantation, with improved functional status and quality of life. (Thoratec HeartMate II Left Ventricular Assist System [LVAS] for Bridge to Cardiac Transplantation; NCT00121472).

Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38α MAPK pathway

Patients with primary (AL) cardiac amyloidosis suffer from progressive cardiomyopathy with a median survival of less than 8 months and a 5-year survival of <10%. Contributing to this poor prognosis is the fact that these patients generally do not tolerate standard heart failure therapies. The molecular mechanisms underlying this deadly form of heart disease remain unclear. Although interstitial amyloid fibril deposition of Ig light chain proteins is a major cause of cardiac dysfunction in AL cardiac amyloidosis, we have previously shown that amyloid precursor proteins directly impair cardiac function at the cellular and isolated organ levels, independent of fibril formation. In this study, we report that amyloidogenic light chain (AL-LC) proteins provoke oxidative stress, cellular dysfunction, and apoptosis in isolated adult cardiomyocytes through activation of p38 mitogen-activated protein kinase (MAPK). AL-LC–induced p38 activation was found to be independent of the upstream MAPK kinase, MKK3/6, and instead depends upon transforming growth factor-β-activated protein kinase-1 binding protein-1 (TAB1)-mediated p38α MAPK autophosphorylation. Treatment of cardiomyocytes with SB203580, a selective p38 MAPK inhibitor, significantly attenuated AL-LC–induced oxidative stress, cellular dysfunction, and apoptosis. Our data provide a unique mechanistic insight into the pathogenesis of AL-LC cardiac toxicity and suggest that TAB1-mediated p38α MAPK autophosphorylation may serve as an important event leading to cardiac dysfunction and subsequent heart failure.

A comparison of cardiac troponin T and creatine kinase-MB for patient evaluation after cardiac surgery

OBJECTIVES The aim of this study was to assess the role of serum markers of myocardial necrosis after cardiac surgery. BACKGROUND The role of serum troponin T (TnT) and creatine kinase-MB (CK-MB) for the risk stratification of patients after cardiac surgery remains undefined. METHODS Serum levels of TnT and CK-MB were measured from 224 patients every 8 h after cardiac surgery. The results of serum cardiac marker testing were correlated with adverse events, including new myocardial infarction (MI), cardiogenic shock or death. Univariable analysis identified factors predictive of complications, while stepwise logistic regression identified independent predictors of postoperative complications. RESULTS Cardiac marker elevation was universal after cardiac surgery. At all time points measured, compared with those patients without complications, the TnT levels from patients with complications were more significantly elevated (all: p < 0.0005). In contrast, among identically timed specimens, the levels of CK-MB from complicated patients were less reliably discriminatory. Multivariable analysis suggested that a TnT level in the highest quintile (> or = 1.58 ng/ml) was the strongest predictor of complications, including death (post-op, odds ratio [OR] = 31.0, 95% confidence interval [CI] = 3.67 to 263.1, p = 0.002) or shock (post-op: OR = 18.9, 95% CI = 2.29 to 156.1, p = 0.006; 18 h to 24 h: OR = 30.7, 95% CI = 3.75 to 250.7, p = 0.001), as well as the composite end points of death/MI (18 h to 24 h: OR = 60.1, 95% CI = 7.34 to 492.1, p < 0.0005), shock/MI (post-op: OR = 23.3, 95% CI = 2.82 to 191.4, p = 0.003; 18 h to 24 h: OR = 37.8, 95% CI = 4.66 to 307.3, p = 0.001) or death/shock/MI (post-op: OR = 20.0, 95% CI = 2.81 to 142.0, p = 0.003; 18 h to 24 h: OR = 67.4, 95% CI = 6.96 to 652.3, p < 0.0005). In contrast, in the presence of TnT, the results of CK-MB measurement added no independent prognostic information. CONCLUSIONS Troponin T is superior to CK-MB for the prediction of impending complications after cardiac surgical procedures.

Perioperative Echocardiographic Examination for Ventricular Assist Device Implantation

Ventricular assist devices (VADs) are systems for mechanical circulatory support of the patient with severe heart failure. Perioperative transesophageal echocardiography is a major component of patient management, and important for surgical and anesthetic decision making. In this review we present the rationale and available data for a comprehensive echocardiographic assessment of patients receiving a VAD. In addition to the standard examination, device-specific pre-, intra-, and postoperative considerations are essential to the echocardiographic evaluation. These include: (a) the pre-VAD insertion examination of the heart and large vessels to exclude significant aortic regurgitation, tricuspid regurgitation, mitral stenosis, patent foramen ovale, or other cardiac abnormality that could lead to right-to-left shunt after left VAD placement, intracardiac thrombi, ventricular scars, pulmonic regurgitation, pulmonary hypertension, pulmonary embolism, and atherosclerotic disease in the ascending aorta; and to assess right ventricular function; and (b) the post-VAD insertion examination of the device and reassessment of the heart and large vessels. The examination of the device aims to confirm completeness of device and heart deairing, cannulas alignment and patency, and competency of device valves using two-dimensional, and color, continuous and pulsed wave Doppler modalities. The goal for the heart examination after implantation should be to exclude aortic regurgitation, or an uncovered right-to-left shunt; and to assess right ventricular function, left ventricular unloading, and the effect of device settings on global heart function. The variety of VAD models with different basic and operation principles requires specific echocardiographic assessment targeted to the characteristics of the implanted device.

Cardiac Transplantation Followed by Dose-intensive Melphalan and Autologous Stem-cell Transplantation for Light Chain Amyloidosis and Heart Failure

Background. Patients with light chain (AL) amyloidosis who present with severe heart failure due to cardiac involvement rarely survive more than 6 months. Survival after cardiac transplantation is markedly reduced due to the progression of amyloidosis. Autologous stem-cell transplantation (ASCT) has become a common therapy for AL amyloidosis, but there is an exceedingly high treatment-related mortality in patients with heart failure. Methods. We developed a treatment strategy of cardiac transplant followed by ASCT. Twenty-six patients were evaluated, and of 18 eligible patients, nine patients underwent cardiac transplantation. Eight of these patients subsequently received an ASCT. Results. Six of seven evaluable patients achieved a complete hematologic remission, and one achieved a partial remission. At a median follow-up of 56 months from cardiac transplant, five of seven patients are alive without recurrent amyloidosis. Their survival is comparable with 17,389 patients who received heart transplants for nonamyloid heart disease: 64% in nonamyloid vs. 60% in amyloid patients at 7 years (P=0.83). Seven of eight transplanted patients have had no evidence of amyloid in their cardiac allograft. Conclusions. This demonstrates that cardiac transplantation followed by ASCT is feasible in selected patients with AL amyloidosis and heart failure, and that such a strategy may lead to improved overall survival.

Endoscopic versus open saphenous vein harvest: a comparison of postoperative wound complications

BACKGROUND Wound complications associated with long incisions used to harvest the greater saphenous vein are well documented. Recent reports suggest that techniques of endoscopic vein harvest may result in decreased wound complications. A prospective, nonrandomized study was developed to compare outcomes of open versus endoscopic vein harvest procedures. METHODS There were 106 patients in the open vein harvest group, and 154 patients in the endoscopic vein harvest group. Patient characteristics and demographics were similar in both groups. Wound complications identified were dehiscence, drainage for greater than 2 weeks postoperatively, cellulitis, hematoma, and seroma/lymphocele. RESULTS Wound complications were significantly less in the endoscopic vein harvest group (9 of 133, 6.8%) versus the open vein harvest group (26 of 92, 28.3%), p less than 0.001. By multivariable analysis with logistic regression, the open vein harvest technique was the only risk factor for postoperative leg wound complication (relative risk 4.0). CONCLUSIONS Endoscopic vein harvest offered improved patient outcomes in terms of wound healing compared with the open vein harvest technique.

Protein Aggregates and Novel Presenilin Gene Variants in Idiopathic Dilated Cardiomyopathy

Background— Heart failure is a debilitating condition resulting in severe disability and death. In a subset of cases, clustered as idiopathic dilated cardiomyopathy (iDCM), the origin of heart failure is unknown. In the brain of patients with dementia, proteinaceous aggregates and abnormal oligomeric assemblies of &bgr;-amyloid impair cell function and lead to cell death. Methods and Results— We have similarly characterized fibrillar and oligomeric assemblies in the hearts of iDCM patients, pointing to abnormal protein aggregation as a determinant of iDCM. We also showed that oligomers alter myocyte Ca2+ homeostasis. Additionally, we have identified 2 new sequence variants in the presenilin-1 (PSEN1) gene promoter leading to reduced gene and protein expression. We also show that presenilin-1 coimmunoprecipitates with SERCA2a. Conclusions— On the basis of these findings, we propose that 2 mechanisms may link protein aggregation and cardiac function: oligomer-induced changes on Ca2+ handling and a direct effect of PSEN1 sequence variants on excitation-contraction coupling protein function.

Results of bioprosthetic versus mechanical aortic valve replacement performed with concomitant coronary artery bypass grafting

BACKGROUND Concomitant coronary artery disease with aortic valve disease is an established risk factor for diminished late survival. This study evaluated the results of bioprosthetic (BAVR) or mechanical aortic valve replacement (MAVR) performed with coronary artery bypass grafting (CABG). METHODS From January 1984 through July 1997, combined AVR + CABG was performed in 750 consecutive patients; 469 received BAVR and 281 received MAVR. BAVR recipients were significantly older (mean age, 75 vs 65 years), and had more nonelective operations, congestive heart failure, peripheral vascular disease, preoperative intraaortic balloons, lower cardiac indices, more severe aortic stenosis, less aortic regurgitation, and more extensive coronary artery disease. RESULTS Early complications included operative mortality, 32 patients (4.3% total: 3.8% BAVR and 5.0% MAVR); perioperative infarction, 10 (1.3%); and perioperative stroke, 22 (2.9%). Significant multivariable predictors of early mortality were age, perioperative infarction or stroke, nonelective operation, operative year, ventricular hypertrophy, and need for intraaortic balloon. Ten-year actuarial survival was 41.7% for all patients. Predicted survival for age- and gender-matched cohorts from the general population versus observed survival were BAVR, 45% versus 36%; MAVR, 71% versus 48% (survival differences BAVR 9% vs MAVR 23%, p < 0.007). Significant multivariable predictors of late mortality included age, congestive failure, perioperative stroke, extent of coronary disease, peripheral vascular disease, and diabetes. Valve type was not significant. Ten-year actuarial freedom from valve-related complications were (BAVR vs MAVR) structural deterioration, 95% versus 100%, p = NS; thromboembolism, 86% versus 84%, p = NS; anticoagulant bleeding, 93% versus 88%, p < 0.005; reoperation, 98% versus 98%, p = NS. CONCLUSIONS AVR + CABG has diminished late survival despite the type of prosthesis inserted. Although valve type did not predict late mortality, mechanical AVR was associated with worse survival compared with predicted and more valve-related complications due to anticoagulation requirements.

Surgical management and long-term outcomes for acute ascending aortic dissection

OBJECTIVE We sought to assess early and late survival and cardiovascular-specific mortality after surgical repair of acute ascending aortic dissection and the effect of differences in surgical technique, patient characteristics, and preoperative diagnostic testing. METHODS Between 1979 and 2003, 195 consecutive patients underwent repair for acute ascending aortic dissection within 2 weeks of the onset of symptoms. Mean follow-up was 7.0 +/- 5.9 years (range, 0-26 years) and was 100% complete. RESULTS Patients were aged 62 +/- 15 years on average and were mostly male (66%) and hypertensive (69%). Risk of death early and late after the operation decreased over the study period, with hospital mortality decreasing from 21% to 4% when comparing the first and most recent quartiles (P = .007, chi(2) test for trend). At 1, 5, 10, and 20 years postoperatively, survival was 84%, 69%, 55%, and 30%, respectively, and freedom from cardiovascular death was 86%, 80%, 71%, and 51%, respectively. Additional independent risk factors for death were older age (P < .001), renal dysfunction (P < .003), syncope (P = .007), and peripheral vascular disease (P = .006). During the study period, echocardiographic and computed tomographic diagnostic imaging replaced routine aortic angiographic analysis, and operative techniques involved more frequent use of open distal anastomoses, retrograde cerebral perfusion, earlier restoration of antegrade perfusion, and a conservative approach to aortic arch repair. Freedom from reoperation on the aorta or aortic valve was 93% and 84% at 5 and 10 years, respectively. CONCLUSIONS Early and late survival after repair of acute ascending aortic dissection has improved progressively over 25 years in association with noticeable changes in preoperative and intraoperative management. Aortic reoperations were infrequent during follow-up.

Young Patients With Nonischemic Cardiomyopathy Have Higher Likelihood of Left Ventricular Recovery During Left Ventricular Assist Device Support

BACKGROUND Recovery of ventricular function during left ventricular assist device (LVAD) support allowing device explantation occurs infrequently. We explored the hypothesis that certain patient profiles are more likely to exhibit LV recovery during LVAD support. METHODS AND RESULTS A retrospective analysis of data from the HeartMate II bridge to transplant (BTT) and destination therapy (DT) trials was conducted, including 490 BTT, 600 DT, and 18 compassionate-use patients. Of the 1,108 patients, 20 (1.8%; 10 BTT, 10 DT) were explanted owing to LV recovery. The median age was 33 years, and 12 patients (60%) were <40 years of age. History of heart failure was <1 year for 11 patients (61%), and the primary etiology was nonischemic (90%). Of the patients with nonischemic etiologies and <1-year history of heart failure, 13% were explanted. Three patients required LVAD reimplantation; of the remaining 17, 16 remain alive. At follow-up (median 510 days), the mean ejection fraction was 42% (20%-67%) and the mean left ventricular end-diastolic diameter was 55 ± 8 mm. At the 2-year follow-up (n = 13), patients were New York Heart Association functional class I or II and overall survival rate was 85 ± 11%. CONCLUSIONS The results of this study suggest that LV recovery is most likely to occur in young patients (<40 years) with nonischemic cardiomyopathy of <1 year duration. Two-year postexplant survival was excellent.