Joyce, Lyle D.

Abstract Heart failure (HF) is a major cause of hospitalization and mortality worldwide. Ventricular assist devices (VADs) represent an alternative to cardiac transplantation for advanced HF. The main FDA-approved VAD (HeartMate III, Abbott), while effective, requires major cardiac surgery to insert the inflow cannula into the cardiac apex, and is associated with numerous co-morbidities and re-hospitalizations related to continuous flow and an external drive line and power supply. Mi-VAD, Inc. aspires to improve outcomes and quality of life with a miniature, minimally invasive, pulsatile, transcutaneously-powered VAD that is implanted above the aortic valve and/or the pulmonary valve and offering a wide range of hemodynamic support suitable for both advanced-stage and less advanced HF. Through its unique placement, there is the potential for right ventricular and biventricular cardiac assist for patients with restrictive cardiomyopathy and HFpEF for whom current VAD therapy is ineffective. Mi-VAD, Inc. has achieved proof of concept with its prototype, providing pulsatile ECG gated cardiac assist up to 10L/minute. Following initial bench top performance testing and in vivo efficacy and safety studies future work will focus on the development of wireless charging capability and conducting GLP builds for verification, regulatory clearance and commercialization. Additional technical development will focus on AI-driven hemodynamic optimization using multimodal physiologic sensing towards patient-specific digital twin of the Mi-VAD platform.

Objectives: CABG and PCI are used for revascularization of multivessel coronary artery disease (MVCAD). However, limited information is available comparing the rates of in-hospital and 30-day major adverse cardiac and cerebrovascular event (early MACCE), including early death, stroke, myocardial infarction (MI), and repeat revascularization, among patients with multiple arterial CABG (MultArt) vs PCI. Methods: We reviewed 12,615 MVCAD patients with isolated primary CABG or PCI from 1993 through 2009. CABG patients (n=6,667) were grouped by number of arterial grafts into left internal mammary artery/saphenous vein (LIMA/SV) (n=5,712) or MultArt (n=955); PCI patients (n=5,948) into balloon angioplasty (BA) (n=1,020), bare metal stent (BMS) (n=3,242), and drug-eluting stent (DES) (n=1,686). Results: Early MACCE rate was significantly greater for PCI than CABG (8.5% vs 4.1% [P<.001]) and lower for MultArt than LIMA/SV or PCI (1.5% vs 4.5% and 8.5%, respectively [P<.001]). Stroke and early death rates were higher in CABG vs PCI (2.2% vs 0.4% [P<.001], and 1.5% vs 1.0% [P=0.01], respectively), whereas MI and repeat revascularization were lower (0.5% vs 6.0% and 0.3% vs 2.2%, respectively [P<.001]). Stroke and early death were similar in MultArt and PCI and lower vs LIMA/SV (0.6% and 0.4% vs 2.6%, and 0.5% and 1.0% vs 1.7%, respectively [P<.001]); MI and repeat revascularization rates were similar in MultArt and LIMA/SV and lower vs PCI (0.4% and 0.6% vs 6.0%, and 0.3% and 0.3% vs 2.3%, respectively [P<.001]). In propensity score-matched analysis, CABG had significantly improved early MACCE rate compared with BA (4.7% vs 13.2% [P<.001]), BMS (4.3% vs 8.3% [P<.001]), and DES (2.9% vs 5.5% [P=.008]), and MultArt compared with PCI (1.8% vs 7.8% [P<.001]) fig. Conclusions: In MVCAD patients undergoing isolated primary revascularization, CABG conferred lower early MACCE rate vs PCI. Early MACCE rate was markedly decreased after MultArt compared with LIMA/SV, BA, BMS, and DES.

Introduction: While left ventricular assist devise (LVAD) support improves the prognosis of end-stage heart failure (HF) patients, the long-term outcomes remains suboptimal. Improved outcomes may occur with organ protection including reverse myocardial remodeling. Cenderitide (CDNP) is a Mayo engineered designer natriuretic peptide (NP) that co-activates particulate guanylyl cyclase A and B receptors and functions via the second messenger cGMP. We reported a NP deficient state in the heart with LVAD support which lays the rationale for NP replacement therapy with Cenderitide which has cardiorenal protective actions in experimental HF. We sought to determine if Cenderitide co-therapy would be safe and activate cGMP in patients with LVAD support. Hypothesis: Acute single dose of subcutaneous (SQ) Cenderitide will be safe and activate cGMP in patients with LVAD support. Methods: Stable HF patients with LVAD support (Heartmate II, all males) were enrolled in a cross-over design comparing SQ placebo and low (Low-C, 5 ug/kg, n=8) or high dose (High-C, 10 ug/kg, n=8) Cenderitide (Capricor Therapeutics) administration. Vital signs, plasma C(D)NP, cGMP, Aldosterone (Aldo), and NT-proBNP levels were measured before or after drug administration over 24 hours. All parameters in Cenderitide group were adjusted by those in placebo. Results: Both Low-C and High-C group demonstrated significantly increased plasma C(D)NP and cGMP levels for 2 hours after drug injection and those in High-C group showed more prolonged and higher increases than Low-C group. Mean arterial pressure (MAP) in Low-C did not show any changes but in High-C group tended to be lower for 18 hours but this was not significant. Plasma Aldo and NT-proBNP levels in Low-C group did not show any change but those in High-C group tended to be lower after drug injection s similar to the change in MAP. No adverse events were observed in the study. Conclusions: SQ Cenderitide was successfully absorbed, activated cGMP and well tolerated in patients with LVAD support. High dose Cenderitide may have cardiac unloading effects suggested by decreases in NT-proBNP. Further clinical trial for efficacy is warranted to clarify cardiorenal protective effects of Cenderitide in the LVAD population to improve outcomes.

Background: Left ventricle assist device (LVAD) support, a well established therapy in advanced CHF, improves renal function assessed by creatinine. While renal function in large numbers of continuous flow (CF) LVADs vs pulsatile flow (PF) LVADs has been evaluated at 3 mo., long term studies are needed with large numbers of CF vs PF devices. To date longer term analysis comparing renal function in CF vs PF devices have relied on a small number of CF devices. We evaluated renal function assessed by creatinine in a large number of CF (HM II) (n=119) devices and compared this to renal function in a group of subjects treated with PF devices (HM XVE) (n=8) at 6 mo. post implant. Our aim was to evaluate change in creatinine between 3 and 6 months in these groups. Methods and Results: Plasma creatinine was evaluated at 3 and 6 months in two groups: subjects with CF HM II (n=119) and PF LVAD (HM XVE, n=8). The data were collected from two centers in patients undergoing implant for destination or bridge to transplant therapy. Baseline creatinine was higher in the HM XVE group at baseline (BL), and decreased at 3 mo. (1.7 [1.1-2.1] vs 1.1 [0.8-1.5] mg/dL, p<0.05). BL creatine in the HM II group decreased at 3 mo as well (1.2 [1-1.5] vs 1.1 [0.9-1.3] mg/dL, p,0.05). Between 3 and 6 months there was no difference in degree of creatinine change in CF vs PF, however both groups had an increase in Creatinine in this time frame: PF (1.1 [0.8-1.5] vs 1.35 [1.05-1.9] mg/dL, p<0.05); CF (1.1 [0.9-1.3] vs 1.2 [0.92-1.4] mg/dL, p<0.05). Conclusion: This is the first study to demonstrate with large numbers of CF LVAD that creatinine does not incrementally increase between 3 and 6 mo. in comparison to PF LVAD. Further studies are required with large numbers of continuos flow LVADs evaluating the comparative effect of long term continuous flow vs pulsatile flow. Additionally, it remains important to identify surrogates of pulsatility in subjects with continuous flow devices and evaluate prognostic impact on renal function long term.

Objectives. The use of the left internal mammary artery (IMA) in revascularization of multivessel coronary artery disease has been shown to improve survival following coronary artery bypass graft surgery (CABG), however the incremental survival benefit of multiple arterial grafts is still debated. Methods. We reviewed outcome of 8,622 pt that had isolated primary CABG for multivessel disease from 1993 to 2009.Pt were stratified according to the number of arterial grafts; (1) single IMA plus saphenous vein (SV) IMA/SV group (n=7,435; 83% 3VD) and (2) multiple arterial (MultArt) group (n=1,187; 74% 3VD) Results. Early mortality rate was 0.8% (n=10) in the MultArt group and 2.1% (n=154) in the IMA/SV group (P=0.004). However, the difference was not statistically significant (P=0.996) after adjusting for age, gender, chronic lung disease, renal failure, PVD, MI, EF, and number of diseased vessels. Late survival was significantly greater for the MultArt group compared to IMA/SV group (5-, 10- and 15-year survival rates were 95%, 84% and 71% versus 85%, 61% and 35% p<0.001). MultArt subgroups with the use of bilateral internal mammary artery (BIMA)/SV (n=589) and BIMA only (n=271), had significantly improved 15-years survival (97%, 86%, 76% and 94%, 82%, 75% at 5-, 10- and 15-years, p<0.001), and BIMA/RA (n=147) and LIMA/RA (n=169), had significantly greater 10-years survival (95%, 84% and 93%, 78% at 5- and 10-years, p<0.001) compared to IMA/SV group. In multivariate analysis, use of multiple arterial grafts remained a strong independent predictor of survival (HR=0.78, 95% CI 0.66 - 0.93, p=0.006). Conclusion. Use of the right IMA or radial artery in addition to the left IMA is associated with significantly better overall and late survival compared with single IMA and saphenous vein in patients with two and three-vessel disease undergoing isolated CABG.

BACKGROUND: The immunologic risk associated with preformed donor-specific allo-antibodies (DSA) against human leukocyte antigens (HLA) in heart transplant (HTX) recipients is unclear. The goal of this study was to evaluate potential role of DSA on the progression of cardiac allograft vasculopathy (CAV) in HTX recipients. METHODS: The presence of DSA against HLA was evaluated using solid phase Single Antigen Bead assay (One Lambda, Inc., Canoga Park, CA; Luminex platform) before transplant in 35 HTX recipients. Using alloantibody specification analysis, 11% (4/35) and 20% (7/35) had DSA against donor Class I and II HLA respectively including the one patient who had both (DSA I & II+) . 71% (25/35) of patients had no demonstrable DSA (DSA-). All patients had negative cytotoxicity cross match. Baseline three-dimensional intravascular ultrasound studies (3D IVUS) were performed at 1.0 [0.18, 1.4] year after transplant. Follow up 3D IVUS exams were performed 0.92 [0.85, 1.04] years after the baseline exam. RESULTS: The increase in mean plaque (media and intima) volume (PV) was accelerated in the DSA II+ group as compared to the DSA- group (0.87±1.9 mm (3)/mm vs. 0.16±1.8 mm (3)/mm) but the vessel volume index (follow up vessel volume/ baseline vessel volume) was similar between groups (1.08±0.5 vs. 1.09± 0.4; p=0.9). Plaque index (PI) (PV/vessel volume x 100 [%]) increased significantly in the DSA II+ group (17.9±6.3%) but not in the DSA- group (-13.6±13.2%, P=0.02). None of these values were significant in the DSA I+ only group. Treatment with Sirolimus did not affect PI progression between the DSA II+ and DSA- groups (PI progression: 15.9±8.7% vs. -11.7±7.1%, P=0.03). Age, gender, lipid and uric acid levels, prevalence of diabetes, ischemic time, time between IVUS examinations, the use of steroids, mycophenolate vs. azathioprine or calcineurin inhibitors vs. sirolimus were not different between the groups (P>0.4 for all). CONCLUSIONS: Heart transplant recipients with clearly defined anti-Class II DSA are at risk for accelerated cardiac allograft vasculopathy. Whether interventions to minimize the risk of DSA such as virtual crossmatch, desensitization and complement inhibition will retard CAV remains to be proven.

Background: Left ventricular assist device (LVAD) implantation is a new therapy for advanced heart failure (HF). The number of HF patients eligible for LVAD and the cardiology providers’ comfort level with referral for LVAD remains unclear. Objective: To assess provider perception of LVAD candidacy and LVAD referral patterns in consecutive HF patients. Methods: Providers completed a survey for each HF patient seen between March 1, 2013 and April 26, 2013. The survey listed standard LVAD candidacy criteria and asked 1) if a patient was an LVAD candidate (yes, no, unsure); 2) reasons patients were not LVAD candidates (check list, table); and 3) whether the patient had been referred for LVAD evaluation (yes, no, unsure). Results: Patients (n=522) were seen in a tertiary HF outpatient clinic (n=357; 68%), a tertiary HF inpatient service (n=36; 7%), a tertiary general cardiology service (n=45; 9%) or a community based outpatient cardiac clinic (n=84; 16%) Median age of patients was 73 years and 65% were male. Provider assessment of LVAD candidacy was “no” in 443 (85%), “yes” in 35 (7%) and “unsure” in 43 (8%) with ineligibility for LVAD attributed to multiple concerns (Table). Ninety percent of patients considered “too old” for LVAD were over 78 years of age. Provider designation of LVAD candidacy as yes or unsure varied across practice setting: tertiary HF outpatient clinic, 12%; tertiary HF inpatient service, 42%; tertiary general cardiology service, 22%; and community based outpatient cardiac clinic, 13%. In patients with a provider designation of LVAD candidacy as yes or unsure (n=78), only 21 (27%) patients had been referred for LVAD evaluation. Conclusion: When provided with LVAD candidacy criteria, providers indicated 15% of HF patients were (7%) or were possibly (8%) LVAD candidates but indicated that few patients had undergone a formal LVAD evaluation. These data suggest that measures to improve evaluation of HF patients for LVAD are needed.

Introduction: Recent reports have documented an abrupt increase in 3-month confirmed HeartMate II left ventricular assist device (LVAD) thrombosis beginning in 2011 without a plateau observed to date. Because very little data exist from multi-institutional efforts, we report our experience. Methods: From January 2004 to December 2013, 516 pt underwent HeartMate II LVAD implant at three institutions (University of Michigan (n=254), Mayo Clinic Rochester (n=205), and Vanderbilt Heart and Vascular Institute (n=57)). Median age at implant was 60 yr (range, 18-82) and 428 (83%) were male. Confirmed pump thrombosis at 3 months was defined as thrombus found in the blood-contacting surfaces of the pump at the time of urgent transplant, device exchange or autopsy. Pt without at least 3 months of follow-up were excluded. Results: Confirmed pump thrombosis occurred in 9 pt within 3 months post implant. The incidence was greatest in the year 2012 (5.3%). Following this peak, the incidence of 3-month confirmed pump thrombosis decreased significantly to 2.9% (Figure). Significant differences in preoperative characteristics between patients with pump thrombosis and without thrombosis included female sex (36% vs. 16%, p=0.01), bridge to transplant (77% vs. 54%, p=0.03), atrial fibrillation (55% vs. 32%, p=0.04), and preop platelet count (231,000 vs. 172,000, p<0.001). Follow-up was available in all for a total of 857 patient years of support. At a median follow-up of 1.2 years (max., 9.8 years), a similar proportion of patients were alive (73% vs. 74%, p=0.9). Conclusions: We report a recent decrease in early, confirmed HeartMate II LVAD thrombosis to historically observed levels, which is disparate to recent reports. While we identified several differences in clinical characteristics between patient groups, the issue of pump thrombosis is complex and multifactorial. Most importantly, our findings demonstrate the need for more granular analyses from collaborative efforts.

Introduction: Frailty has recently been shown to be associated with increased risk of death after continuous-flow left ventricular assist device (CF-LVAD) implantation as destination therapy (DT), but no data exists specifically analyzing its association with specific early and late adverse events. Methods: Between February 2007 and May 2014, 251 patients (205 male) underwent primary implantation of CF-LVAD at our institution; 157 (63%) were implanted as DT and preoperative frailty assessment was available in 96 pt. Frailty was identified in 58/96 (60%) patients according to the deficit index (31 impairments, disabilities and comorbidities) and defined as > 25% deficits. Age (67 vs. 64 years, p=0.12), male sex (79% vs. 87%, 0.63), chronic kidney disease (64% vs. 63%, p=0.74), creatinine (1.7 vs. 1.5, p=0.1), hemoglobin (11.6 vs. 11.5, p=0.98), and albumin levels (3.7 vs. 3.8, p=0.53) were similar between frail and non-frail pt, while diabetes (59% vs. 13%, p<0.001), ischemic etiology (64% vs. 45%, p=0.04), and preop balloon pump (50% vs. 26%, p=0.01) were significantly different. Results: All patients underwent CF-LVAD implantation and cardiopulmonary bypass time was similar between groups (102 vs. 111 min., p=0.3). There were no significant differences in early adverse events between frail and non-frail pt, including inotrope duration (120 vs. 96 hr., p=0.11), right ventricular failure (19% vs. 13%, p=0.44), respiratory failure (26% vs. 18%, p=0.34), acute renal failure (16% vs. 13%, p=0.69), and hepatic dysfunction (16% vs. 13%, p=0.69). Median length of stay (20 vs. 16 days, p=0.25) and early mortality (12% vs. 8%, p=0.48) were also similar. During a median follow up of 2 years with 224 patient/years of support, any GI bleed (43% vs. 42%, p=0.79), any thromboembolic event (34% vs. 39%, p=0.74), and driveline infection (10% vs. 26%, p=0.052). Conclusions: In this select cohort of patients, frailty did not portend higher risk of adverse events after CF-LVAD implantation for DT despite prior observation that late survival is reduced in these patients. These findings are extremely important in patient selection and counseling of patients prior to LVAD implantation.

Abstract Abstract 2273 Background: Continuous flow left ventricular assist device (CF-LVAD) recipients have high tendency of post-surgical gastrointestinal (GI) bleeding. We previously described the loss of high molecular weight VWF multimers (HMWM), due to either an accelerated clearance or enhanced cleavage of the HMWM, in most CF-LVAD recipients (Ann Thorac Surg. 90:1263–9). However, besides the tedious plasma VWF multimer analysis, neither VWF ristocetin cofactor nor collagen binding activity assay provides sufficient sensitivity for detecting such an acquired VWF abnormality (AVWA). In this study, we examined a new automated latex particle-enhanced immunoturbidimetric VWF activity assay (VWF:Lx) for its ability of detecting CF-LVAD-AVWA. We also analyzed the VWF pro-peptide (VWF:pp) to explored the potential mechanism of CF-LVAD-AVWA. Design: As part of an on-going prospective multicenter study, pre- and post-CF-LVAD implantation (7, 30 days and 5–7 months) blood samples were collected from 15 LVAD recipients (median age 52 years; 10 male and 5 female; 2008∼2009). Plasma VWF antigen (VWF:Ag), VWF:Lx activity, VWF:pp/Ag ratios were measured; and plasma VWF multimer analyses were performed on all available plasma samples. Standard statistical analyses were employed. Result: Loss of VWF HMWM was observed in 3 patients prior to CF-LVAD implantation and virtually all patients after surgery. VWF:Ag, VWF:Lx or VWF:pp/Ag ratios of the pre- and post-implantation samples were not significantly different (P> 0.1). However, VWF:Lx/Ag ratios of the post-implantation samples were significantly decreased (P<0.05). At a cut off of 0.8, the VWF:Lx/Ag ratio has a 90% sensitivity and specificity for detecting AVWA. Conclusions: VWF:Lx/Ag ratio has excellent sensitivity and specificity in detecting CF-LVAD-AVWA, and its impact on predicting post-surgical bleeding tendency in CF-LVAD recipients is being investigated. The distinct CF-LVAD-AVWA is most likely caused by enhanced cleavage, rather than clearance, of the HMWM. Disclosures: No relevant conflicts of interest to declare.