O. Howard Frazier

Advanced Heart Failure Treated with Continuous-Flow Left Ventricular Assist Device

BACKGROUND Patients with advanced heart failure have improved survival rates and quality of life when treated with implanted pulsatile-flow left ventricular assist devices as compared with medical therapy. New continuous-flow devices are smaller and may be more durable than the pulsatile-flow devices. METHODS In this randomized trial, we enrolled patients with advanced heart failure who were ineligible for transplantation, in a 2:1 ratio, to undergo implantation of a continuous-flow device (134 patients) or the currently approved pulsatile-flow device (66 patients). The primary composite end point was, at 2 years, survival free from disabling stroke and reoperation to repair or replace the device. Secondary end points included survival, frequency of adverse events, the quality of life, and functional capacity. RESULTS Preoperative characteristics were similar in the two treatment groups, with a median age of 64 years (range, 26 to 81), a mean left ventricular ejection fraction of 17%, and nearly 80% of patients receiving intravenous inotropic agents. The primary composite end point was achieved in more patients with continuous-flow devices than with pulsatile-flow devices (62 of 134 [46%] vs. 7 of 66 [11%]; P<0.001; hazard ratio, 0.38; 95% confidence interval, 0.27 to 0.54; P<0.001), and patients with continuous-flow devices had superior actuarial survival rates at 2 years (58% vs. 24%, P=0.008). Adverse events and device replacements were less frequent in patients with the continuous-flow device. The quality of life and functional capacity improved significantly in both groups. CONCLUSIONS Treatment with a continuous-flow left ventricular assist device in patients with advanced heart failure significantly improved the probability of survival free from stroke and device failure at 2 years as compared with a pulsatile device. Both devices significantly improved the quality of life and functional capacity. (ClinicalTrials.gov number, NCT00121485.)

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).

Transmyocardial laser revascularization: Results of a multicenter trial with transmyocardial laser revascularization used as sole therapy for end-stage coronary artery disease ☆ ☆☆ ★ ★★ ♢

BACKGROUND Transmyocardial laser revascularization was used as the sole therapy for patients with ischemic heart disease not amenable to percutaneous transluminal coronary angioplasty or coronary artery bypass grafting. This technique uses a carbon dioxide laser to create transmyocardial channels for direct perfusion of the ischemic heart. METHODS Since 1992, 200 patients, at eight hospitals in the United States, have undergone transmyocardial laser revascularization. The patients have a combined 1560 months of follow-up for an average of 10 +/- 3 months per patient. Their age was 63 +/- 10 years and their ejection fraction was 47% +/- 12%. Eighty-two percent had at least one previous bypass graft operation and 38% had a prior angioplasty. Preoperatively, the patients underwent nuclear single photon emission computed tomography perfusion scans to identify the extent and severity of their ischemia. These scans were repeated at 3, 6, and 12 months. Angina class, admissions for angina, and medications were recorded. RESULTS The perioperative mortality was 9%. Angina class decreased significantly from before treatment to 3, 6, and 12 months (p < 0.001). Likewise, there was a significant decrease in the number of perfusion defects in the treated left ventricular free wall. Concomitantly, there was a significant decrease in the number of admissions for angina in the year after the procedure when compared with the year before treatment (2.5 vs 0.5 admissions per patient-year). CONCLUSION These combined results indicate that transmyocardial laser revascularization provides angina relief, decreases hospital admissions, and improves perfusion in patients with severe coronary artery disease.

Low Thromboembolism and Pump Thrombosis With the HeartMate II Left Ventricular Assist Device: Analysis of Outpatient Anti-coagulation

BACKGROUND The HeartMate II (Thoratec, Pleasanton, CA) is an effective bridge to transplantation (BTT) but requires anti-coagulation with warfarin and aspirin. We evaluated the risk of thromboembolism and hemorrhage related to the degree of anti-coagulation as reflected by the international normalized ratio (INR). METHODS INRs were measured monthly for 6 months in all discharged HeartMate II BTT patients and at an event. Each INR was assigned to ranges of INRs. Adverse events analyzed were ischemic and hemorrhagic stroke, pump thrombosis, and bleeding requiring surgery or transfusion. Events were correlated to the INR during the event and at the start of the month. RESULTS In 331 patients discharged on support, 10 had thrombotic events (9 ischemic strokes, 3 pump thromboses), and 58 had hemorrhagic events (7 strokes, 4 hemorrhages requiring surgery, and 102 requiring transfusions). The median INR was 2.1 at discharge and 1.90 at 6 months. Although the incidence of stroke was low, 40% of ischemic strokes occurred in patients with INRs < 1.5 and 33% of hemorrhagic strokes were in patients with INRs > 3.0. The highest incidence of bleeding was at INRs > 2.5. CONCLUSIONS The rate of thromboembolism during long-term outpatient support with the HeartMate II is low. The low number of thrombotic events appears to be offset by a greater number of hemorrhagic events. An appropriate target INR is 1.5 to 2.5 in addition to aspirin therapy. In patients having recurrent episodes of bleeding, the risk of lowering the target INR appears to be small.

HeartWare ventricular assist system for bridge to transplant: Combined results of the bridge to transplant and continued access protocol trial

BACKGROUND The HeartWare Ventricular Assist System (HeartWare Inc, Framingmam, MA) is a miniaturized implantable, centrifugal design, continuous-flow blood pump. The pivotal bridge to transplant and continued access protocols trials have enrolled patients with advanced heart failure in a bridge-to-transplant indication. METHODS The primary outcome, success, was defined as survival on the originally implanted device, transplant, or explant for ventricular recovery at 180 days. Secondary outcomes included an evaluation of survival, functional and quality of life outcomes, and adverse events. RESULTS A total of 332 patients in the pivotal bridge to transplant and continued access protocols trial have completed their 180-day primary end-point assessment. Survival in patients receiving the HeartWare pump was 91% at 180 days and 84% at 360 days. Quality of life scores improved significantly, and adverse event rates remain low. CONCLUSIONS The use of the HeartWare pump as a bridge to transplant continues to demonstrate a high 180-day survival rate despite a low rate of transplant. Adverse event rates are similar or better than those observed in historical bridge-to-transplant trials, despite longer exposure times due to longer survival and lower transplant rates.

Post–cardiac transplant survival after support with a continuous-flow left ventricular assist device: Impact of duration of left ventricular assist device support and other variables

OBJECTIVE Although left ventricular assist devices (LVADs) are associated with excellent outcomes in patients with end-stage heart failure, there are conflicting reports on posttransplant survival in these patients. Furthermore, prior studies with pulsatile LVADs have shown that transplantation, either early (<6 weeks) or late (>6 months) after LVAD implantation, adversely affected post-cardiac transplant survival. We sought to determine factors related to posttransplant survival in patients supported with continuous-flow LVADs. METHODS The HeartMate II LVAD (Thoratec Corporation, Pleasanton, Calif) was implanted in 468 patients as a bridge to transplant at 36 centers in a multicenter trial. Patients who underwent transplantation after support were stratified by demographics: gender, age, etiology, body mass index, duration of device support, and by adverse events during support. The median age was 54 years (range 18-73 years); 43% had ischemic etiology, and 18% were women. Survival was determined at the specific intervals of 30 days and 1 year after transplantation. RESULTS Of 468 patients, 250 (53%) underwent cardiac transplant after a median duration of LVAD support of 151 days (longest: 3.2 years), 106 (23%) died, 12 (2.6%) recovered ventricular function and the device was removed, and 100 (21%) were still receiving LVAD support. The overall 30-day and 1-year posttransplant survivals were 97% and 87%. There were no significant differences in survival based on demographic factors or LVAD duration of less than 30 days, 30 to 90 days, 90 to 180 days, and more than 180 days. Patients requiring more than 2 units of packed red blood cells in 24 hours during LVAD support had a statistically significant decreased 1-year survival (82% vs 94%) when compared with patients who did not require more than 2 units of packed red blood cells in 24 hours during LVAD support (P = .03). There was a trend for slightly lower survival at 1 year in patients with percutaneous lead infections during LVAD support versus no infection (75% vs 89%; P = .07). CONCLUSIONS Post-cardiac transplant survival in patients supported with continuous-flow devices such as the HeartMate II LVAD is equivalent to that with conventional transplantation. Furthermore, posttransplant survival is not influenced by the duration of LVAD support. The improved durability and reduced short- and long-term morbidity associated with the HeartMate II LVAD has reduced the need for urgent cardiac transplantation, which may have adversely influenced survival in the pulsatile LVAD era. This information may have significant implications for changing the current United Network for Organ Sharing criteria regarding listing of heart transplant candidates.

Resection of Aortic Arch Aneurysms: A Comparison of Hypothermic Techniques in 60 Patients

Hypothermic circulatory arrest has been used to facilitate resection of aneurysms of the aortic arch. During a five-year period, two methods of hypothermic arrest were compared in 60 patients. In Group 1, 20 patients underwent deep hypothermia (14 degrees to 18 degrees C) and circulatory arrest to allow repair of the transverse arch under optimal conditions. A hospital mortality of 50% occurred and was attributed to uncontrolled hemorrhage and cerebral or cardiac complications. In Group 2, modified techniques were employed in 40 patients and included moderate levels of hypothermia (22 degrees to 26 degrees C) and simplified operative methods, which reduced the duration of circulatory arrest and shortened the length of perfusion. Pretreatment of plasma-soaked Dacron grafts by autoclaving eliminated serious bleeding problems. A marked improvement in patient survival (90%) and reduction in postoperative complications were observed after adoption of these modifications. The improved results in the present series have reconfirmed our belief that this type of intervention is the preferred approach to aneurysms of the aortic arch.

Hyperlipidemia after heart transplantation: Report of a 6-year experience, with treatment recommendations

Mean plasma lipid values in 100 patients who survived greater than 3 months after heart transplantation increased significantly at 3 months over pretransplantation values: total cholesterol from 168 +/- 7 to 234 +/- 7 mg/dl, low density lipoprotein (LDL) cholesterol from 111 +/- 6 to 148 +/- 6 mg/dl, high density lipoprotein (HDL) cholesterol from 34 +/- 1 to 47 +/- 1 mg/dl and triglycerides from 107 +/- 6 to 195 +/- 10 mg/dl. There were no significant increases after this time. The LDL cholesterol values reamined greater than or equal to 130 mg/dl in 64% of patients and triglyceride values remained greater than or equal to 200 mg/dl in 41% of patients 6 months after postoperative dietary instructions. Beginning in 1985, select patients whose total cholesterol values remained greater than 300 mg/dl despite 6 months of dietary intervention were treated with lovastatin given alone in a high dose (40 to 80 mg/day) or in combination with another hypolipidemic agent. Four of the five patients so treated developed rhabdomyolysis; two of the four had acute renal failure. Beginning in 1988, a second protocol--lovastatin at 20 mg/day as monotherapy--was used in patients who despite dietary intervention had total cholesterol greater than 240 mg/dl (mean follow-up 13 months). In the 15 patients so treated, mean total cholesterol decreased from 299 +/- 10 mg/dl before treatment with lovastatin to 235 +/- 9 mg/dl during treatment (21% reduction, p less than 0.001) and mean LDL cholesterol was reduced from a baseline value of 190 +/- 10 to 132 +/- 12 mg/dl during treatment (31% reduction, p less than 0.001). In this study, lovastatin at a dose of less than or equal to 20 mg/day as monotherapy was a well tolerated, effective treatment for hyperlipidemia after heart transplantation. It did not result in rhabdomyolysis and required no alteration in immunosuppressive therapy. However, the dose should not exceed 20 mg/day and combination therapy with either gemfibrozil or nicotinic acid should be avoided, even if the target LDL cholesterol value is not reached.

Downregulation of Myocardial Myocyte Enhancer Factor 2C and Myocyte Enhancer Factor 2C–Regulated Gene Expression in Diabetic Patients With Nonischemic Heart Failure

Background—In animal studies, diabetes has been shown to induce changes in gene expression of key regulators in cardiac energy metabolism and calcium homeostasis. In the present study, we tested the hypothesis that metabolic gene expression in nonischemic failing hearts of diabetic patients differs from that in nonischemic failing hearts of nondiabetic patients. Methods and Results—Left ventricular tissue was obtained from nonfailing hearts (n=6) and from nonischemic failing hearts of patients with or without type 2 diabetes. Myocardial transcript levels of key regulators in energy substrate metabolism (glucose transporter 1, glucose transporter 4, pyruvate dehydrogenase kinase 4, peroxisome proliferator–activated receptor &agr;, muscle carnitine palmitoyl transferase-1, medium-chain acyl-CoA dehydrogenase, and uncoupling protein 3), calcium homeostasis (sarcoplasmic reticulum Ca2+-ATPase [SERCA2a], phospholamban, and cardiac ryanodine receptor), and contractile function (myosin heavy chain &agr;) were measured using real-time quantitative reverse transcription–polymerase chain reaction. In addition, we measured myocyte enhancer factor 2C (MEF2C) and SERCA2a protein levels. Only MEF2C regulated transcripts (glucose transporter 4, SERCA2a, and myosin heavy chain &agr;) were lower in the diabetic group compared with the nondiabetic group. MEF2C protein content was also decreased. Conclusion—MEF2C and MEF2C-regulated genes are decreased in the failing hearts of diabetic patients. This transcriptional mechanism may contribute to the contractile dysfunction in heart failure patients with diabetes.

Outcomes of a multicenter trial of the Levitronix CentriMag ventricular assist system for short-term circulatory support

OBJECTIVE The Levitronix CentriMag (Levitronix LLC, Waltham, Mass) ventricular assist system is designed for temporary left, right, or biventricular support. Advantages include ease of use, excellent reliability, and low thrombosis risk,. which may allow wider application of short-term support and improved outcomes in patients with cardiogenic shock. This multi-institutional study evaluated safety, effectiveness, and outcomes of the CentriMag in patients with cardiogenic shock. METHODS Thirty-eight patients were supported at 7 centers. Patients included 12 after cardiotomy, 14 after myocardial infarction, and 12 with right ventricular failure after implantable left ventricular assist device placement. Devices were implanted in left (n = 8), right (n = 12), or biventricular (n = 18) configuration. Support was continued until recovery, transplantation, or implantation of long-term ventricular assist device. RESULTS Mean support duration for the entire cohort (n = 38) was 13 days (1-60 days), with 47% of patients (18/38) surviving 30 days after device removal. Mean CentriMag biventricular support (n = 18) duration was 15 days (1-60 days), with 44% (8/18) surviving at 30 days. Mean CentriMag right ventricular support with a commercially available left ventricular assist device (n = 12) duration was 14 days (1-29 days), with 58% (7/12) surviving at 30 days. Complications included bleeding (21%), infection (5%), respiratory failure (3%), hemolysis (5%), and neurologic dysfunction (11%). There were no CentriMag or pump failures. CONCLUSIONS In this preliminary study, the CentriMag provided short-term support for patients with cardiogenic shock with a low incidence of device-related complications and no device failures.