Nir Uriel

Acquired von Willebrand Syndrome After Continuous-Flow Mechanical Device Support Contributes to a High Prevalence of Bleeding During Long-Term Support and at the Time of Transplantation

OBJECTIVES The objective of the study was to determine the prevalence of bleeding during continuous-flow left ventricular assist device support and to identify potential mechanisms for those bleeding events. BACKGROUND Bleeding is frequently reported with continuous-flow left ventricular assist devices and may result from anticoagulation coupled with bleeding diathesis such as acquired von Willebrand syndrome. Accordingly, the prevalence of coagulation abnormalities including laboratory assessment for von Willebrand syndrome, bleeding events during device support, and at heart transplantation were evaluated. METHODS A retrospective study in all HeartMate II (HM II) (Thoratec Corp., Pleasanton, California) patients who underwent implantation between April 1, 2004, and August 1, 2009, was performed. Bleeding was defined as the need for transfusion >7 days after device insertion of 1 U of packed red blood cells. Transfusion at heart transplantation was compared with that in HeartMate XVE patients. RESULTS Seventy-nine HM II devices were implanted. Anticoagulation included warfarin in 68.3%, aspirin in 55.7%, and dipyridamole in 58.2% of the patients. Of the patients, 44.3% had bleeding episodes at 112 ± 183 days after left ventricular assist device implantation, with 50% experiencing an event within 2 months. Gastrointestinal bleeding was the most frequent event. At the index event, the international normalized ratio averaged 1.67 ± 0.53, and the platelet count was 237 ± 119 × 10(9)/l. Comparison of the transfusion requirements at heart transplantation of 35 HM II patients with 62 HeartMate XVE patients demonstrated twice the transfusion requirements in HM II patients (packed red blood cells, 6.3 ± 0.8 U vs. 3.8 ± 0.5 U; platelets, 12.5 ± 5.4 U vs. 8.6 ± 6.4 U; fresh frozen plasma, 9.6 ± 4.9 U vs. 4.9 ± 3.6 U; and cryoprecipitate, 4.3 ± 3.6 U vs. 2.2 ± 3.5 U; p < 0.05 for all). High molecular weight von Willebrand factor multimers were measured in 31 HM II patients and were reduced in all patients; 18 of these 31 (58%) patients had bleeding. CONCLUSIONS Patients with the HM II had a high incidence of bleeding events during device support and at heart transplantation. All HM II patients had reduced high molecular weight von Willebrand factor multimers. The role of these abnormalities in the high incidence of bleeding deserves further investigation. Furthermore, alterations in anticoagulation should be considered during device support and before surgery in patients supported with the HM II.

Development of a Novel Echocardiography Ramp Test for Speed Optimization and Diagnosis of Device Thrombosis in Continuous-Flow Left Ventricular Assist Devices: The Columbia Ramp Study

OBJECTIVES This study sought to develop a novel approach to optimizing continuous-flow left ventricular assist device (CF-LVAD) function and diagnosing device malfunctions. BACKGROUND In CF-LVAD patients, the dynamic interaction of device speed, left and right ventricular decompression, and valve function can be assessed during an echocardiography-monitored speed ramp test. METHODS We devised a unique ramp test protocol to be routinely used at the time of discharge for speed optimization and/or if device malfunction was suspected. The patients left ventricular end-diastolic dimension, frequency of aortic valve opening, valvular insufficiency, blood pressure, and CF-LVAD parameters were recorded in increments of 400 rpm from 8,000 rpm to 12,000 rpm. The results of the speed designations were plotted, and linear function slopes for left ventricular end-diastolic dimension, pulsatility index, and power were calculated. RESULTS Fifty-two ramp tests for 39 patients were prospectively collected and analyzed. Twenty-eight ramp tests were performed for speed optimization, and speed was changed in 17 (61%) with a mean absolute value adjustment of 424 ± 211 rpm. Seventeen patients had ramp tests performed for suspected device thrombosis, and 10 tests were suspicious for device thrombosis; these patients were then treated with intensified anticoagulation and/or device exchange/emergent transplantation. Device thrombosis was confirmed in 8 of 10 cases at the time of emergent device exchange or transplantation. All patients with device thrombosis, but none of the remaining patients had a left ventricular end-diastolic dimension slope >-0.16. CONCLUSIONS Ramp tests facilitate optimal speed changes and device malfunction detection and may be used to monitor the effects of therapeutic interventions and need for surgical intervention in CF-LVAD patients.

A Fully Magnetically Levitated Circulatory Pump for Advanced Heart Failure

Background Continuous‐flow left ventricular assist systems increase the rate of survival among patients with advanced heart failure but are associated with the development of pump thrombosis. We investigated the effects of a new magnetically levitated centrifugal continuous‐flow pump that was engineered to avert thrombosis. Methods We randomly assigned patients with advanced heart failure to receive either the new centrifugal continuous‐flow pump or a commercially available axial continuous‐flow pump. Patients could be enrolled irrespective of the intended goal of pump support (bridge to transplantation or destination therapy). The primary end point was a composite of survival free of disabling stroke (with disabling stroke indicated by a modified Rankin score >3; scores range from 0 to 6, with higher scores indicating more severe disability) or survival free of reoperation to replace or remove the device at 6 months after implantation. The trial was powered for noninferiority testing of the primary end point (noninferiority margin, ‐10 percentage points). Results Of 294 patients, 152 were assigned to the centrifugal‐flow pump group and 142 to the axial‐flow pump group. In the intention‐to‐treat population, the primary end point occurred in 131 patients (86.2%) in the centrifugal‐flow pump group and in 109 (76.8%) in the axial‐flow pump group (absolute difference, 9.4 percentage points; 95% lower confidence boundary, ‐2.1 [P<0.001 for noninferiority]; hazard ratio, 0.55; 95% confidence interval [CI], 0.32 to 0.95 [two‐tailed P=0.04 for superiority]). There were no significant between‐group differences in the rates of death or disabling stroke, but reoperation for pump malfunction was less frequent in the centrifugal‐flow pump group than in the axial‐flow pump group (1 [0.7%] vs. 11 [7.7%]; hazard ratio, 0.08; 95% CI, 0.01 to 0.60; P=0.002). Suspected or confirmed pump thrombosis occurred in no patients in the centrifugal‐flow pump group and in 14 patients (10.1%) in the axial‐flow pump group. Conclusions Among patients with advanced heart failure, implantation of a fully magnetically levitated centrifugal‐flow pump was associated with better outcomes at 6 months than was implantation of an axial‐flow pump, primarily because of the lower rate of reoperation for pump malfunction. (Funded by St. Jude Medical; MOMENTUM 3 ClinicalTrials.gov number, NCT02224755.)

Prevalence of de novo aortic insufficiency during long-term support with left ventricular assist devices

BACKGROUND Left ventricular assist devices (LVADs) are increasingly used as long-term therapy for end-stage heart failure patients. We compared the prevalence of aortic insufficiency (AI) after HeartMate II (HMII) vs HeartMate XVE (HMI) support and assessed the role of aortic root diameter and aortic valve opening in the development of AI. METHOD Pre-operative and post-operative echocardiograms of 93 HMI and 73 HMII patients who received implants at our center between January 2004 and September 2009 were retrospectively reviewed. After excluding patients with prior or concurrent surgical manipulation of the aortic valve, with baseline AI, or without baseline echoes, 67 HMI and 63 HMII patients were studied. AI was deemed significant if mild to moderate or greater. Pathology reports were reviewed for 77 patients who underwent heart transplant. RESULTS AI developed in 4 of 67 HMI (6.0%) and in 9 of 63 HMII patients (14.3%). The median times to AI development were 48 days for HMI patients and 90 days for HMII patients. For patients who remained on device support at 6 and 12 months, freedom from AI was 94.5% and 88.9% in HMI patients and 83.6% and 75.2% in HMII patients (log rank p = 0.194). Aortic root diameters, as determined by echocardiography for the patients with AI, trended to be larger at baseline (3.43 ± 0.43 vs 3.15 ± 0.40; p = 0.067) and follow-up (3.58 ± 0.54 vs 3.29 ± 0.50; p = 0.130) compared with those who did not have AI. Aortic root circumferences were assessed directly by a pathologist in those patients who underwent transplant and were significantly larger in HMII patients who had developed AI compared with those patients who did not (8.44 ± 0.89 vs 7.36 ± 1.02 cm; p = 0.034). Lastly, AI was more common in patients whose aortic valve did not open (11 of 26 vs 1 of 14; p = 0.03). CONCLUSION Aortic insufficiency occurs frequently in patients who receive continuous-flow support with a HMII LVAD, and may be associated with aortic root diameter enlargement and aortic valve opening. These findings warrant a more thorough preoperative patient evaluation and additional studies to investigate the factors, that may be associated with AI development.

Clinical outcome of mechanical circulatory support for refractory cardiogenic shock in the current era

BACKGROUND Mortality for refractory cardiogenic shock (RCS) remains high. However, with improving mechanical circulatory support device (MCSD) technology, the treatment options for RCS patients are expanding. We report on a recent 5-year single-center experience with MCSD for treatment of RCS. METHODS This study was a retrospective review of adult patients who required an MCSD due to RCS in the past 5 years. We excluded those patients with post-cardiotomy shock and post-transplant cardiac graft dysfunction. In the setting of RCS, a short-term ventricular assist device (VAD) was inserted as a bridge-to-decision device. Veno-arterial extracorporeal membrane oxygenation (VA ECMO) was chosen in cases of unknown neurologic status, complete hemodynamic collapse or severe coagulopathy. RESULTS From January 2007 through January 2012, 90 patients received an MCSD for RCS, 21 (23%) of whom had active cardiopulmonary resuscitation (CPR). The etiology of RCS included acute myocardial infarction in 49% and acute decompensated heart failure in 27%. Mean age was 53±14 years, 71% were male, and 60% had an intra-aortic balloon pump. The initial approach utilized was short-term VAD in 49% and VA ECMO in 51%. Median length of support was 8 days (IQR 4 to 18 days). Exchange to implantable VAD was performed in 26% of patients. Other destinations included myocardial recovery in 18% and heart transplantation in 11%. Survival to hospital discharge was 49%. Multivariate analysis showed ongoing CPR to be an independent risk factor for mortality (OR = 5.79, 95% CI 1.285 to 26.08, p = 0.022). CONCLUSIONS In the current era, roughly half of the patients who need an MCSD for RCS survive, and roughly half of these survivors require an implantable VAD. Ongoing CPR is predictive of in-hospital mortality.

Ventricular arrhythmias and implantable cardioverter-defibrillator therapy in patients with continuous-flow left ventricular assist devices: Need for primary prevention?

OBJECTIVES This study sought to evaluate the prevalence and significance of ventricular arrhythmia (VA) and the role of an implantable cardioverter-defibrillator (ICD) in patients supported by a continuous-flow left ventricular assist device (CF-LVAD). BACKGROUND VAs are common in patients supported by CF-LVADs but prospective data to support the routine use of ICDs in these patients are lacking. METHODS All patients supported by long-term CF-LVAD receiving care at our institution were enrolled. The ICDs were interrogated at baseline and throughout prospective follow-up. The VA was defined as ventricular tachycardia/fibrillation lasting >30 s or effectively terminated by appropriate ICD tachytherapy. The primary outcome was the occurrence of VA >30 days after CF-LVAD implantation. RESULTS Ninety-four patients were enrolled; 77 had an ICD and 17 did not. Five patients with an ICD had it deactivated or a depleted battery not replaced during the study. Twenty-two patients had a VA >30 days after LVAD implantation. Pre-operative VA was the major predictor of post-operative arrhythmia. Absence of pre-operative VA conferred a low risk of post-operative VA (4.0% vs. 45.5%; p < 0.001). No patients discharged from the hospital without an ICD after CF-LVAD implantation died during 276.2 months of follow-up (mean time without ICD, 12.7 ± 12.3 months). CONCLUSIONS Patients with pre-operative VA are at risk of recurrent VA while on CF-LVAD support and should have active ICD therapy to minimize sustained VA. Patients without pre-operative VA are at low risk and may not need active ICD therapy.

Pre-operative and post-operative risk factors associated with neurologic complications in patients with advanced heart failure supported by a left ventricular assist device

BACKGROUND Neurologic complications (NCs) are the major adverse events after left ventricular assist device (LVAD) surgery. Pre-operative and post-operative factors associated with NCs in patients with LVADs were investigated. METHODS We reviewed 307 consecutive patients undergoing LVAD surgery (167 HeartMate I and 140 HeartMate II devices) at Columbia University Medical Center between November 2000 and December 2010. Clinical characteristics and hemodynamic and laboratory indexes were analyzed. NC was defined according to the Interagency Registry for Mechanically Assisted Circulatory Support definition of neurologic dysfunction, including transient ischemic attack (TIA) and ischemic or hemorrhagic cerebrovascular accident (CVA). RESULTS NCs developed in 43 patients (14.0%) at 91.8 ± 116.3 days post-operatively. The frequency of NC development was similar in HeartMate I and II patients. Patients with NC showed a higher frequency of pre-LVAD CVA history (27.9% vs 15.5%, p = 0.046), lower pre-operative sodium (129.0 ± 7.0 vs 132.1 ± 8.1 mg/dl, p = 0.018) and albumin concentrations (3.5 ± 0.7 vs 3.7 ± 0.6 mg/dl, p = 0.049), lower post-operative hematocrit (34.9% ± 5.1% vs 37.8% ± 6.1%, p = 0.0034), sodium (131.6 ± 7.7 vs 134.4 ± 6.4 mg/dl, p = 0.010) and albumin concentrations (3.7 ± 0.5 vs 3.9 ± 0.5 mg/dl, p = 0.0016), and higher frequency of post-operative infection (39.5% vs 19.3%, p = 0.003) than those without NC. Multiple regression analysis revealed that CVA history (odds ratio, 2.37, 95% confidence interval, 1.24-5.29; p = 0.011) and post-operative infection (odds ratio, 2.99, 95% confidence interval, 1.16-10.49; p = 0.011) were highly associated with NC development. The combination of CVA history, pre-operative and post-operative sodium and albumin, and post-operative hematocrit and infection could discriminate patients developing NCs with a probability of 76.6%. CONCLUSIONS Previous stroke, persistent malnutrition and inflammation, severity of heart failure, and post-LVAD infections are key factors associated with development of NCs after LVAD implantation.

Prevalence, Significance, and Management of Aortic Insufficiency in Continuous Flow Left Ventricular Assist Device Recipients

Background— Aortic insufficiency (AI) is increasingly recognized as a complication of continuous flow left ventricular assist device support; however, its long-term prevalence, clinical significance, and efficacy of potential interventions are not well known. Methods and Results— We studied the prevalence and management of AI in 232 patients with continuous flow left ventricular assist device at our institution. Patients with aortic valve (AV) surgery before left ventricular assist device implantation were excluded from analysis. To examine the prevalence of de novo AI, patients without preoperative AI were divided into a retrospective and a prospective cohort based on whether a dedicated speed optimization study had been performed at the time of discharge. Forty-three patients underwent AV repair at the time of implant, and 3 subsequently developed greater than mild AI. In patients without surgical AV manipulation and no AI at the time of implant, Kaplan–Meier analysis revealed that freedom from greater than mild de novo AI at 1 year was 77.6±4.2%, and that at least moderate AI is expected to develop in 37.6±13.3% after 3 years. Nonopening of the AV was strongly associated with de novo AI development in patients without prospective discharge speed optimization. Seven of 21 patients with at least moderate AI developed symptomatic heart failure requiring surgical intervention. Conclusions— AI is common in patients with continuous flow left ventricular assist devices and may lead to clinical decompensation requiring surgical correction. The prevalence of AI is substantially less in patients whose AV opens, and optimized loading conditions may reduce AI prevalence in those patients in whom AV opening cannot be achieved.

Inflammatory activation: cardiac, renal, and cardio-renal interactions in patients with the cardiorenal syndrome

Although inflammation is a physiologic response designed to protect us from infection, when unchecked and ongoing it may cause substantial harm. Both chronic heart failure (CHF) and chronic kidney disease (CKD) are known to cause elaboration of several pro-inflammatory mediators that can be detected at high concentrations in the tissues and blood stream. The biologic sources driving this chronic inflammatory state in CHF and CKD are not fully established. Traditional sources of inflammation include the heart and the kidneys which produce a wide range of pro-inflammatory cytokines in response to neurohormones and sympathetic activation. However, growing evidence suggests that non-traditional biomechanical mechanisms such as venous and tissue congestion due to volume overload are also important as they stimulate endotoxin absorption from the bowel and peripheral synthesis and release of pro-inflammatory mediators. Both during the chronic phase and, more rapidly, during acute exacerbations of CHF and CKD, inflammation and congestion appear to amplify each other resulting in a downward spiral of worsening cardiac, vascular, and renal functions that may negatively impact patients’ outcome. Anti-inflammatory treatment strategies aimed at attenuating end organ damage and improving clinical prognosis in the cardiorenal syndrome have been disappointing to date. A new therapeutic paradigm may be needed, which involves different anti-inflammatory strategies for individual etiologies and stages of CHF and CKD. It may also include specific (short-term) anti-inflammatory treatments that counteract inflammation during the unsettled phases of clinical decompensation. Finally, it will require greater focus on volume overload as an increasingly significant source of systemic inflammation in the cardiorenal syndrome.

Hemodynamics of Mechanical Circulatory Support.

An increasing number of devices can provide mechanical circulatory support (MCS) to patients with acute hemodynamic compromise and chronic end-stage heart failure. These devices work by different pumping mechanisms, have various flow capacities, are inserted by different techniques, and have different sites from which blood is withdrawn and returned to the body. These factors result in different primary hemodynamic effects and secondary responses of the body. However, these are not generally taken into account when choosing a device for a particular patient or while managing a patient undergoing MCS. In this review, we discuss fundamental principles of cardiac, vascular, and pump mechanics and illustrate how they provide a broad foundation for understanding the complex interactions between the heart, vasculature, and device, and how they may help guide future research to improve patient outcomes.