O.H. Frazier

Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart

In animal models of lipotoxicity, accumulation of triglycerides within cardiomyocytes is associated with contractile dysfunction. However, whether intramyocardial lipid deposition is a feature of human heart failure remains to be established. We hypothesized that intramyocardial lipid accumulation is a common feature of non‐ischemic heart failure and is associated with changes in gene expression similar to those found in an animal model of lipotoxicity. Intramyocardial lipid staining with oil red O and gene expression analysis was performed on heart tissue from 27 patients (9 female) with non‐ischemic heart failure. We determined intramyocardial lipid, gene expression, and contractile function in hearts from 6 Zucker diabetic fatty (ZDF) and 6 Zucker lean (ZL) rats. Intramyocardial lipid overload was present in 30% of non‐ischemic failing hearts. The highest levels of lipid staining were observed in patients with diabetes and obesity (BMI>30). Intramyocardial lipid deposition was associated with an up‐regulation of peroxisome proliferator‐activated receptor a (PPARα) ‐regulated genes, myosin heavy chain β (MHC‐β), and tumor necrosis factor α (TNF‐α). Intramyocardial lipid overload in the hearts of ZDF rats was associated with contractile dysfunction and changes in gene expression similar to changes found in failing human hearts with lipid overload. Our findings identify a subgroup of patients with heart failure and severe metabolic dysregulation characterized by intramyocardial triglyceride overload and changes in gene expression that are associated with contractile dysfunction.—Sharma, S., Adrogue, J. V., Golfman, L., Uray, I., Lemm, J., Youker, K., Noon, G. P., Frazier, O. H., Taegtmeyer, H. Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J. 18, 1692–1700 (2004)

Primary cardiac sarcomas

In marked contrast to benign cardiac tumors, primary cardiac sarcomas occur infrequently. Moreover, there is no uniform approach to treating such patients, and the benefits of postoperative chemotherapy are unclear. Between 1964 and 1989, 21 patients with primary cardiac sarcomas underwent surgical resection alone (n = 7), chemotherapy alone (n = 1), or combined operation and postoperative chemotherapy based on adriamycin (n = 13). Twenty-four operations were performed on 20 patients with relief of symptoms in all. Eleven patients had complete resection. Operative mortality was 8.3% (2/24). Histology and originating chamber(s) included angiosarcoma (n = 7; 6/7 in right atrium, 1 in left atrium), malignant fibrous histocytoma (7; all in left atrium), fibrosarcoma (2; 2/2 in left atrium), rhabdomyosarcoma (2; 1 in left atrium, 1 in right ventricle), leiomyosarcoma (2; 1 in left atrium, 1 in left ventricle); and one undifferentiated sarcoma (right atrium). Overall actuarial survival was 14% at 24 months after resection. Patients with complete resection had a median survival of 24 months compared with only 10 months in all other patients (p = 0.035). Postoperative chemotherapy did not enhance survival in patients with incomplete resection. At this time, aggressive and complete surgical resection seems to offer the best hope for palliation and survival in an otherwise fatal disease.

Left ventricular assist system as a bridge to myocardial recovery

BACKGROUND Despite recent advances in medical therapy, heart transplantation, and mechanical circulatory support, the mortality of patients with congestive heart failure remains high. METHODS Retrospective data on 5 patients were obtained from our hospitals medical records. Each patient was supported by a left ventricular assist system (LVAS) because of severe congestive heart failure. The duration of LVAS support averaged 229 days (range, 46 to 447 days). In 3 patients, the LVAS was removed electively after the patient showed recovery of myocardial function. In the other 2, it was removed because of a malfunction. RESULTS In response to LVAS support, hemodynamic variables were significantly improved. The mean cardiac index increased from 1.45 to 2.69 L x min(-1) x m(-2) (p < 0.001) and the mean left ventricular ejection fraction increased from 0.144 to 0.288 (p < 0.025). All patients were in New York Heart Association functional class IV at LVAS implantation and class I at its explantation. One patient died of noncardiac-related causes 10 days after LVAS removal. The remaining 4 patients are alive and well 35, 33, 14, and 2 months after LVAS removal. CONCLUSIONS In select patients with severe congestive heart failure, mechanical unloading with an LVAS can result in recovery of myocardial function. These patients can return to a normal physical status, thereby avoiding heart transplantation. More research is required to determine optimal modes of LVAS support, to predict which patients are likely to recover, and to assess long-term outcomes.

Surgical treatment of cardiac tumors: A 25-year experience

From 1964 to 1989, we performed operations on 133 patients with cardiac tumors. There were 58 male and 75 female patients ranging in age from three days to 81 years; 101 were adults, and 32 were children (less than 12 years of age). Primary tumors (102 benign and 12 malignant) were found in 114 patients and metastatic tumors in 19. Symptoms included congestive heart failure, arrhythmias, emboli, and chest pain. Diagnosis was accomplished through angiography, echocardiography, computed tomography, and magnetic resonance imaging. Operative treatment encompassed techniques ranging from biopsy to complete excision (including hypothermic circulatory arrest and cardiac autotransplantation) depending on the site of disease and the extent of involvement. Overall operative survival was 91%. Twelve patients died early (within 30 days of operation), and follow-up was obtained for 110 (90.9%) of the remaining 121 survivors (total patient-years of follow-up, 572.8; mean follow-up, 5.2 years). Of the 20 patients who died late, 15 had malignant disease. Operative survival for patients with primary cardiac malignancies and for those with metastatic disease was 83% and 68.4%, respectively, with 3 and 5 patients, respectively, still living. We advocate an aggressive surgical approach, especially in patients with benign tumors, who can expect an excellent outcome. For patients with malignant or metastatic disease, palliation and cure are also possible if aggressive surgical actions are taken.

Arteriovenous malformation and gastrointestinal bleeding in patients with the HeartMate II left ventricular assist device

BACKGROUND In this study we investigated gastrointestinal (GI) bleeding and its relationship to arteriovenous malformations (AVMs) in patients with the continuous-flow HeartMate II (HMII) left ventricular assist device (LVAD). METHODS The records of 172 patients who received HMII support between November 2003 and June 2010 were reviewed. Patients were considered to have GI bleeding if they had 1 or more of the following symptoms: guaiac-positive stool; hematemesis; melena; active bleeding at the time of endoscopy or colonoscopy; and blood within the stomach at endoscopy or colonoscopy. The symptom(s) had to be accompanied by a decrease of >1 g/dl in the patients hemoglobin level. The location of the bleeding was identified as upper GI tract, lower GI tract or both according to esophagogastroduodenoscopy, colonoscopy, small-bowel enteroscopy or mesenteric angiography. Post-LVAD implantation anti-coagulation therapy consisted of warfarin, aspirin and dipyridamole. RESULTS Thirty-two of the 172 patients (19%) had GI bleeding after 63 ± 62 (range 8 to 241) days of HMII support. Ten patients had GI bleeding from an AVM; these included 3 patients who had 2 bleeding episodes and 2 patients who had 5 episodes each. Sixteen patients had upper GI bleeding (10 hemorrhagic gastritis, 4 gastric AVM, 2 Mallory-Weiss syndrome), 15 had lower GI bleeding (6 diverticulosis, 6 jejunal AVM, 1 drive-line erosion of the colon, 1 sigmoid polyp, 1 ischemic colitis) and 1 had upper and lower GI bleeding (1 colocutaneous and gastrocutaneous fistula). All GI bleeding episodes were successfully managed medically. CONCLUSIONS Arteriovenous malformations can cause GI bleeding in patients with continuous-flow LVADs. In all cases in this series, GI bleeding was successfully managed without the need for surgical intervention.

First use of an untethered, vented electric left ventricular assist device for long-term support.

This report describes the first long-term (505-day) application of the vented electric (VE) HeartMate left ventricular assist device (LVAD) (Thermo Cardiosystems, Inc). The device consists of an abdominally placed, battery-powered titanium blood pump that, in contrast to earlier pneumatically powered systems, allows patients untethered freedom of movement. The batteries last 5 to 8 hours and can be changed on a rotating basis indefinitely. The patient, a 33-year-old man (90 kg, blood type O) with idiopathic cardiomyopathy, experienced end-organ heart failure (New York Heart Association [NYHA] class IV) while he was awaiting heart transplantation. When his hemodynamic criteria met those outlined in the protocol, we implanted the VE-LVAD as a bridge to transplantation. The patient was supported by the device for more than 16 months. His cardiac status returned to NYHA class I, and he was eventually allowed to take day trips outside the hospital as he awaited transplantation. The VE-LVAD enabled the patient to participate in activities such as eating in restaurants, going to movies, and practicing basketball shots. Unfortunately, the patient died suddenly due to a neurological thromboembolic event that occurred on day 503 of VE-LVAD support. The VE-LVAD improved native left ventricular function by chronic unloading, and ventricular remodeling resulted in a more normal configuration anatomically, physiologically, and ultimately, histologically and pathologically.

Clinical experience with an implantable, intracardiac, continuous flow circulatory support device: physiologic implications and their relationship to patient selection

BACKGROUND We have been investigating continuous-flow circulatory support devices for 20 years. Unlike pulsatile assist devices, continuous-flow pumps have a simplified pumping mechanism and they do not require compliance chambers or valves. In the 1980s, clinical experience with the Hemopump proved a high-speed, intravascular, continuous-flow pump could safely augment the circulation. Subsequently, a decade of animal experiments with a larger, longer-term continuous-flow pump (the Jarvik 2000) confirmed the safety and efficacy of intraventricular placement, leading to its clinical application. METHODS We analyzed the physiologic and anatomic effect of using the Jarvik 2000 pump for cardiac support in 23 patients in whom the device was applied as a bridge to transplant under the protocol approved by the Food and Drug Administration Investigational Device Exemption. The device was used as a bridge to transplantation in 20 patients and as destination therapy in 3 patients. RESULTS In the bridge-to-transplant group, 14 patients underwent transplantation, 5 died during the circulatory support period and 1 is in an ongoing study. The support period lasted an average of 90 days. For the survivors, the follow-up period has averaged 16 months. Within the first 48 postoperative hours, the average cardiac index increased by 65% (from 1.77 +/- 0.24 to 2.92 +/- 0.60 L. min(-1). m(-2), p = 0.00000002), the systemic vascular resistance decreased by 42% (from 1604 +/- 427 to 930 +/- 330 dynes/sec per cm(2), p = 0.00001), and the pulmonary capillary wedge pressure (PCWP) decreased by 41.8% (from 23 +/- 5.1 to 13.4 +/- 6.6 mm Hg, p = 0.00009). Similar results were seen for the patients undergoing destination therapy. Cardiac index increased 89.5% (from 1.9 +/- 0.1 to 3.6 +/- 0.6, p = 0.046) and PCWP decreased by 52.2% (from 23 +/- 10 to 11 +/- 2, p = 0.22). In that group, 1 patient died unexpectedly from an accident 382 days after device implantation. The 2 survivors remain in New York Heart Association (NYHA) functional class I at 700 to 952 days after implantation. CONCLUSIONS The Jarvik 2000 can offer effective long-term support for patients with chronic heart failure and NYHA class IV status. However, the new physiology produced by continuous offloading of the heart throughout the cardiac cycle has introduced unique clinical problems. The understanding of the problems generated by this biotechnological interface is essential for obtaining optimal clinical outcomes.

Fibrosis and heart failure

The extracellular matrix (ECM) is a living network of proteins that maintains the structural integrity of the myocardium and allows the transmission of electrical and mechanical forces between the myocytes for systole and diastole. During ventricular remodeling, as a result of iterations in the hemodynamic workload, collagen, the main component of the ECM, increases and occupies the areas between the myocytes and the vessels. The resultant fibrosis (reparative fibrosis) is initially a compensatory mechanism and may progress adversely influencing tissue stiffness and ventricular function. Replacement fibrosis appears at sites of previous cardiomyocyte necrosis to preserve the structural integrity of the myocardium, but with the subsequent formation of scar tissue and widespread distribution, it has adverse functional consequences. Continued accumulation of collagen impairs diastolic function and compromises systolic mechanics. Nevertheless, the development of fibrosis is a dynamic process wherein myofibroblasts, the principal cellular elements of fibrosis, are not only metabolically active and capable of the production and upregulation of cytokines but also have contractile properties. During the process of reverse remodeling with left ventricular assist device unloading, cellular, structural, and functional improvements are observed in terminal heart failure patients. With the advent of anti-fibrotic pharmacologic therapies, cellular therapy, and ventricular support devices, fibrosis has become an important therapeutic target in heart failure patients. Herein, we review the current concepts of fibrosis as a main component of ventricular remodeling in heart failure patients. Our aim is to integrate the histopathologic process of fibrosis with the neurohormonal, cytochemical, and molecular changes that lead to ventricular remodeling and its physiologic consequences in patients. The concept of fibrosis as living scar allows us to envision targeting this scar as a means of improving ventricular function in heart failure patients.

First human use of the Hemopump, a catheter-mounted ventricular assist device

The Hemopump, a catheter-mounted, temporary ventricular assist device, consists of an external electromechanical drive console and a disposable, intraarterial axial-flow pump (21F). Power is transmitted percutaneously to the pump by a flexible drive shaft within the catheter. The device is positioned in the left ventricle by way of the femoral artery approach or through the ascending aorta. Blood is drawn from the left ventricle through the transvalvular inlet cannula and pumped into the aorta. As of December 1988, the Hemopump had successfully supported the circulation of 7 patients (5 men, 2 women) ranging in age from 44 to 72 years (mean age, 59 years) and suffering from cardiogenic shock (cardiac index less than 2.0 L/min/m2). Indications for use included failure to be weaned from cardiopulmonary bypass in 4 patients, acute myocardial infarction in 1, severe cardiac allograft rejection in 1, and donor heart failure in 1. Duration of support ranged from 26 to 113 hours (mean, 66 hours). Although 5 patients demonstrated transient hemolysis, none experienced infection, thrombosis, or vascular injury. Hemodynamic variables improved in all patients during support by the device. As of December 1988, 5 of the 7 patients were alive more than 30 days after support had been discontinued, and 3 of these patients were discharged from the hospital. On the basis of our initial clinical results, the Hemopump, which does not require a major surgical procedure for insertion, provides effective, temporary circulatory support in patients with potentially reversible cardiac failure.

Results of HeartMate II left ventricular assist device implantation on renal function in patients requiring post-implant renal replacement therapy

BACKGROUND Renal function is often compromised in patients with advanced heart failure. METHODS We evaluated renal function in heart failure patients supported by the HeartMate II (Thoratec Corporation, Pleasanton, CA) continuous-flow left ventricular assist device (LVAD) who required renal replacement therapy (RRT) by continuous venovenous hemofiltration dialysis (CVVHD) or hemodialysis, or both. Indications for RRT included oliguria (urine < 400 ml/day) unresponsive to diuretic therapy for > 24 hours with a creatinine level > 2.0 mg/dl or 1.5 times that of the pre-implant creatinine level, severe acidemia, and volume overload. RESULTS Of 107 consecutive patients who underwent HeartMate II implantation at our center and had been supported for > 30 days, 15 (13 men and 2 women) required post-implant RRT. Of the 15 patients, 3 received CVVHD and 12 received CVVHD and hemodialysis. Renal function improved within 2 months of support compared with average values before support (creatinine clearance, 64 ± 39 vs 92 ± 55 ml/min, p = 0.041; glomerular filtration rate, 46.9 ± 20.7 vs 73.2 ± 38.9 ml/min/1.73 m(2); p = 0.032). Renal function improved after HeartMate II implantation in 10 patients, and RRT was removed. Of these 10 patients, 2 underwent heart transplantation 4 months after RRT was removed, 1 underwent heart and kidney transplantation 4 years later, 2 died at home of conditions unrelated to renal function 6 months after RRT was removed, and 5 are awaiting heart transplantation, with good quality of life. CONCLUSIONS In this study, patients who experienced clinical recovery after the LVAD implant had subsequent recovery of renal function after continuous-flow LVAD support.