Reynolds M. Delgado

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.)

Decreased expression of tumor necrosis factor-α in failing human myocardium after mechanical circulatory support: A potential mechanism for cardiac recovery

BACKGROUND An increasing number of observations in patients with end-stage heart failure suggest that chronic ventricular unloading by mechanical circulatory support may lead to recovery of cardiac function. Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine capable of producing pulmonary edema, dilated cardiomyopathy, and death. TNF-alpha is produced in the myocardium in response to volume overload; however, the effects of normalizing ventricular loading conditions on myocardial TNF-alpha expression are not known. We hypothesize that chronic ventricular unloading by the placement of a left ventricular assist device (LVAD) may eliminate the stress responsible for persistent TNF-alpha expression in human failing myocardium. METHODS AND RESULTS Myocardial tissue was obtained from normal hearts and from paired samples of 8 patients with nonischemic end-stage cardiomyopathy at the time of LVAD implantation and removal. Tissue sections were stained for TNF-alpha, and quantitative analysis of the stained area was performed. We found that TNF-alpha content decreased significantly after LVAD support. Furthermore, the magnitude of the changes did not correlate with the length of LVAD support, although greater reductions in myocardial TNF-alpha content were found in patients who were successfully weaned off the LVAD who did not require transplantation. CONCLUSIONS These data show for the first time that chronic mechanical circulatory assistance decreases TNF-alpha content in failing myocardium; furthermore, we suggest that the magnitude of the change may predict which patients will recover cardiac function.

Initial Clinical Experience With the Jarvik 2000 Implantable Axial-Flow Left Ventricular Assist System

Background—Implantable left ventricular assist systems (LVASs) are used for bridging to transplantation, bridging to myocardial improvement, and for permanent circulatory support. Conventional implantable systems have inherent limitations that increase morbidity during support. In contrast, small, efficient, axial-flow pumps, which have been under development for the past decade, have the potential to improve the length and quality of life in patients with severe heart failure. Methods and Results—To assess the safety and clinical utility of the Jarvik 2000, we implanted this device in 10 transplant candidates (mean age 51.3 years) in New York Heart Association (NYHA) class IV. Implantation was achieved through a left thoracotomy during partial cardiopulmonary bypass. The mean support period was 84 days. Within 48 hours postoperatively, the cardiac index increased 43%, pulmonary capillary wedge pressure decreased 52%, systemic vascular resistance decreased significantly, and inotropic support became unnecessary. Eight patients underwent physical rehabilitation and returned to NYHA class I. Their left ventricular dimensions, cardiothoracic ratios, and pressure-volume loop analyses showed good left ventricular unloading. Seven patients underwent transplantation and 3 died during support. No device thrombosis was observed at explantation. Conclusions—The Jarvik 2000 functions as a true assist device by partially unloading the left ventricle, thereby optimizing the patient’s hemodynamics. Our preliminary results indicate that this LVAS may safely provide circulatory assistance for heart transplant candidates.

Prolonged QTc Interval and High B-Type Natriuretic Peptide Levels Together Predict Mortality in Patients With Advanced Heart Failure

Background—The role of QTc interval prolongation in heart failure remains poorly defined. To better understand it, we analyzed the QTc interval duration in patients with heart failure with high B-type natriuretic peptide (BNP) levels and analyzed the combined prognostic impact of prolonged QTc and elevated BNP. Methods and Results—QTc intervals were measured in 241 patients with heart failure who had BNP levels >400 pg/mL. QT interval duration was determined by averaging 3 consecutive beats through leads II and V4 on a standard 12-lead ECG and corrected by using the Bazett formula. QTc intervals were prolonged (>440 ms) in 122 (51%) patients and normal in 119 (49%). The BNP levels in these 2 groups were not significantly different (786±321 pg/mL in the prolonged QTc group versus 733±274 pg/mL in the normal QTc group, P =0.13). During 6 months of follow-up, 46 patients died, 9 underwent transplantation, and 17 underwent left ventricular assist device implantation. The deaths were attributed to pump failure (n=24, 52%), sudden cardiac death (n=18, 39%), or noncardiac causes (n=4, 9%). Kaplan-Meier survival rates were 3 times higher in the normal QTc group than in the prolonged QTc group (P <0.0001). On multivariate analysis, prolonged QTc interval was an independent predictor of all-cause death (P =0.0001), cardiac death (P =0.0001), sudden cardiac death (P =0.004), and pump failure death (P =0.0006). Conclusions—Prolonged QTc interval is a strong, independent predictor of adverse outcome in patients with heart failure with BNP levels >400 pg/mL.

Dobutamine stress echocardiography predicts myocardial improvement in patients supported by left ventricular assist devices (LVADs): Hemodynamic and histologic evidence of improvement before LVAD explantation

BACKGROUND Cardiac function may improve in patients with end-stage heart failure who receive long-term support (>30 days) with left ventricular assist devices (LVADs). Dobutamine stress echocardiography (DSE) has been used to quantitate myocardial recovery in patients with heart failure supported with LVADs. By recording the hemodynamic response with the use of DSE, we evaluated and applied the resulting data to patients receiving LVAD support. METHODS AND RESULTS The study population included 16 patients who underwent LVAD implantation, regained functional capacity on full LVAD support, and tolerated decreased mechanical support with no worsening of dyspnea or fatigue. All 16 patients underwent dobutamine stress with increasing doses of dobutamine (from 5 to 40 mcg/kg/min). Hemodynamics and 2-dimensional (2-D) echocardiography was performed at each dose level. In addition, paired myocardial samples were obtained and analyzed histologically to determine myocyte size and collagen content. Dobutamine stress separated the study population into 2 groups: those who had favorable responses to dobutamine (9/16) and those who had unfavorable responses (i.e., experienced hemodynamic deterioration; 7/16). Favorable dobutamine responses were characterized by improved cardiac index, improved force-frequency relationship in the left ventricle (dP/dt), improved left ventricular ejection fraction, and decreased left ventricular end-diastolic dimension. All 9 favorable responders underwent LVAD explantation, and 6 survived for more than 12 months. In all patients studied, LVAD support resulted in decreased myocyte size (n = 14, 33.9 +/- 0.9 microm before vs 16.6 +/- 0.8 microm after support, p = 0.0001; normal, 5-15 microm) but resulted in no consistent changes in collagen content. CONCLUSIONS Dobutamine stress echocardiography with hemodynamic assessment may be a useful tool in assessing physiologic improvement in myocardial function of patients with end-stage heart failure who receive LVAD support. It may help predict which patients can tolerate LVAD removal. Prospective analysis of cardiac function is now warranted to better define myocardial recovery in patients supported with LVADs.

Cyclooxygenase-2 Inhibitor Treatment Improves Left Ventricular Function and Mortality in a Murine Model of Doxorubicin-Induced Heart Failure

Background—Progression of heart failure after initial myocardial injury is mediated in part by various redundant inflammatory mediators, including the widely expressed cyclooxygenase-2 (COX-2). Because COX-2 inhibitors are useful in treating many inflammation-mediated diseases, we asked whether COX-2 inhibition can attenuate heart failure progression. Methods and Results—Heart failure was experimentally induced in 100 mice by administration of doxorubicin (4 mg · kg−1 · wk−1 for 6 weeks). Beginning at day 42, mice were fed daily with either COX-2 inhibitor–containing mice chow (n=50) or plain mice chow (controls; n=50). Left ventricular ejection fraction was evaluated as a measure of heart failure by a novel method of transthoracic echocardiography (with intravascular ultrasound catheters) at baseline and on days 42, 56, and 70. From baseline to study termination, left ventricular ejection fraction in COX-2 inhibitor–treated mice decreased significantly less than in control mice (9% versus 29%, P <0.01). Mortality was significantly lower for COX-2 inhibitor–treated mice than for control mice (18% versus 38%, P <0.01). These results were confirmed in a revalidation study in COX-2 inhibitor–treated mice (n=25) and controls (n=25). That study revealed that the hearts from control mice weighed roughly the same as hearts from COX-2 inhibitor–treated mice but showed more extensive signs of cardiomyopathy (as determined by pathological analysis by an independent, blinded observer) and higher levels of COX-2 proteins (as determined by immunoblotting [6442±1635 versus 4300±2408 arbitrary units, P <0.022]). Conclusions—COX-2 inhibitors can attenuate the progression of heart failure in a murine model of doxorubicin-induced heart failure.

Continuous axial-flow left ventricular assist device (Jarvik 2000) maintains kidney and liver perfusion for up to 6 months

BACKGROUND The Jarvik 2000 axial flow left ventricular assist device (LVAD), under development for the past decade, has the potential to support patients temporarily until cardiac transplantation or as a permanent circulatory support, without the size limitations of other implantable systems. METHODS To assess its ability to perfuse the kidneys and liver, we monitored renal and hepatic function in 10 patients who received the Jarvik 2000 LVAD as a bridge to transplantation. Left ventricular assistance was maintained for up to 214 days (> 6 months), and renal and hepatic function were monitored at least weekly. RESULTS Renal function before LVAD implantation in these patients was normal in 7 (creatinine, < 1.5) and moderately impaired in 3 (creatinine, 1.2 to 2.0). Hepatic function was normal in 7 patients before LVAD implantation (total bilirubin< 1.2; serum glutamic-oxaloacetic transaminase (SGOT), < 40; serum glutamic-pyruvic transaminase (SGPT), < 50) and normal at the time of transplantation in all 10 patients. Of the 3 patients with abnormal hepatic function before LVAD implantation, 1 patient had also had moderate renal dysfunction. CONCLUSIONS Despite reduced pulsatility, the Jarvik 2000 LVAD improves or maintains excellent renal and hepatic function during periods of circulatory assistance in patients awaiting transplantation.

Use of the Flowmaker (Jarvik 2000) Left Ventricular Assist Device for Destination Therapy and Bridging to Transplantation

The Flowmaker left ventricular assist device (formerly known as the Jarvik 2000) is an axial-flow pump that provides continuous flow from the left ventricle to the aorta. Designed for either temporary or permanent use, the Flowmaker is undergoing clinical trials in the United States and Europe. The goal of this therapy is to provide adequate circulatory flow while partially reducing the left ventricular size and end-diastolic pressure. This gives the native ventricle an opportunity to remodel itself. Those who benefit the most from this technology are patients who require only true left ventricular assistance rather than total capture of the left ventricular output. Because of the Flowmaker’s simplicity and safety of implantation, as well as the absence of late pump failure, its use may be justified in severely impaired class III and IV (but not preterminal) heart failure patients.

Mechanical Circulatory Support for Advanced Heart Failure Where Does It Stand in 2003

Today, the lifetime risk of developing heart failure is 1 in 5 for both men and women.1 This high risk underscores the need for effective therapies to treat terminal heart failure unresponsive to conventional treatment. Cardiac transplantation, when possible, offers not only significant palliation but also a real opportunity for meaningful long-term survival. However, posttransplantation mortality and morbidity have improved little over the past decade, and because of the shortage of suitable donor organs, this therapy will never have more than a minimal epidemiological impact on heart failure. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. To expand the therapeutic options for treating end-stage heart failure, the National Institutes of Health initiated research in the mid-1970s designed to develop mechanical circulatory support (MCS) devices that could provide destination therapy for this condition. The devices developed from this program were first used clinically, however, as bridges to transplantation in the mid-1980s. These implantable MCS devices have now been employed as a bridge to transplantation in more than 4000 patients worldwide. In 2002, on the basis of the results of the Randomized Evaluation of Mechanical Assistance for the Treatment of Chronic Heart failure (REMATCH) trial,2 implantable MCS systems were approved for destination therapy in patients who were not acceptable candidates for cardiac transplantation. Despite these advances, numerous questions remain about the ultimate goals of MCS and the role of this technology in treating heart failure. Who are the best candidates for these devices, and what should be the therapeutic goals in each case? What adjuncts can be expected to maximize the benefits of MCS? How can future devices best be developed and studied? To illustrate where this technology stands in 2003 and how it can be expected to develop, …

Use of the Percutaneous Left Ventricular Assist Device in Patients with Severe Refractory Cardiogenic Shock as a Bridge to Long-term Left Ventricular Assist Device Implantation

BACKGROUND For patients with persistent cardiogenic shock refractory to intraaortic balloon pump (IABP) support, there are only limited means of resuscitation and bridging to surgical left ventricular assist device (LVAD) implantation. Extracorporeal membrane oxygenation and emergency surgical approaches have been attempted but are associated with significant morbidity and mortality. We evaluated the efficacy of a percutaneous left ventricular assist device (PVAD) as a bridge to LVAD implantation in patients in cardiogenic shock refractory to IABP and pressor support. METHODS Between May 2003 and April 2006, at our institution, 18 patients in severe refractory cardiogenic shock received a PVAD as a bridge to LVAD placement or orthotopic heart transplantation. Six patients had ischemic cardiomyopathy, and 12 had nonischemic cardiomyopathy. At the time of PVAD placement, 17 were receiving IABP support, and 10 were undergoing cardiopulmonary resuscitation. RESULTS The mean duration of PVAD support was 4.2 +/- 2.5 days. During this time, the cardiac index improved from 0.86 +/- 0.66 to 2.50 +/- 0.93 liters/min/m2 (p < 0.001), systolic blood pressure improved from 72 +/- 11 to 98 +/- 15 mm Hg (p = 0.001), and systemic mixed venous oxygenation improved from 37 +/- 7 to 62 +/- 6 mm Hg (p < 0.001). We terminated life support in 4 of the 18 patients before LVAD placement; 14 were successfully bridged to LVAD or heart transplantation. The mortality rate was 27% at 30 days and 33% at 6 months. There were no PVAD-associated deaths. CONCLUSION In patients with terminal hemodynamic collapse, PVAD support is an effective bridging therapy to LVAD and appears to be a viable alternative to other invasive methods of support.