Maryjane Farr

An Open-Label Dose Escalation Study to Evaluate the Safety of Administration of Nonviral Stromal Cell-Derived Factor-1 Plasmid to Treat Symptomatic Ischemic Heart Failure

Rationale: Preclinical studies indicate that adult stem cells induce tissue repair by activating endogenous stem cells through the stromal cell-derived factor-1:chemokine receptor type 4 axis. JVS-100 is a DNA plasmid encoding human stromal cell-derived factor-1. Objective: We tested in a phase 1, open-label, dose-escalation study with 12 months of follow-up in subjects with ischemic cardiomyopathy to see if JVS-100 improves clinical parameters. Methods and Results: Seventeen subjects with ischemic cardiomyopathy, New York Heart Association class III heart failure, with an ejection fraction ⩽40% on stable medical therapy, were enrolled to receive 5, 15, or 30 mg of JVS-100 via endomyocardial injection. The primary end points for safety and efficacy were at 1 and 4 months, respectively. The primary safety end point was a major adverse cardiac event. Efficacy end points were change in quality of life, New York Heart Association class, 6-minute walk distance, single photon emission computed tomography, N-terminal pro-brain natruretic peptide, and echocardiography at 4 and 12 months. The primary safety end point was met. At 4 months, all of the cohorts demonstrated improvements in 6-minute walk distance, quality of life, and New York Heart Association class. Subjects in the 15- and 30-mg dose groups exhibited improvements in 6-minute walk distance (15 mg: median [range]: 41 minutes [3–61 minutes]; 30 mg: 31 minutes [22–74 minutes]) and quality of life (15 mg: –16 points [+1 to –32 points]; 30 mg: –24 points [+17 to –38 points]) over baseline. At 12 months, improvements in symptoms were maintained. Conclusions: These data highlight the importance of defining the molecular mechanisms of stem cell-based tissue repair and suggest that overexpression of stromal cell-derived factor-1 via gene therapy is a strategy for improving heart failure symptoms in patients with ischemic cardiomyopathy.

Effects of Continuous-Flow Versus Pulsatile-Flow Left Ventricular Assist Devices on Myocardial Unloading and Remodeling

Background— Continuous-flow left ventricular assist devices (LVAD) are increasingly used for patients with end-stage heart failure (HF). We analyzed the effects of ventricular decompression by continuous-flow versus pulsatile-flow LVADs on myocardial structure and function in this population. Methods and Results— Sixty-one patients who underwent LVAD implantation as bridge-to-transplant were analyzed (pulsatile-flow LVAD: group P, n=31; continuous-flow LVAD: group C, n=30). Serial echocardiograms, serum levels of brain natriuretic peptide (BNP), and extracellular matrix biomarkers (ECM) were compared between the groups. Myocardial BNP and ECM gene expression were evaluated in a subset of 18 patients. Postoperative LV ejection fraction was greater (33.2±12.6% versus 17.6±8.8%, P<0.0001) and the mitral E/E′ was lower (9.9±2.6 versus 13.2±3.8, P=0.0002) in group P versus group C. Postoperative serum levels of BNP, metalloproteinases (MMP)-9, and tissue inhibitor of MMP (TIMP)-4 were significantly lower in group P compared with group C (BNP: 552.6±340.6 versus 965.4±805.7 pg/mL, P<0.01; MMP9: 309.0±220.2 versus 475.2±336.9 ng/dL, P<0.05; TIMP4: 1490.9±622.4 versus 2014.3±452.4 ng/dL, P<0.001). Myocardial gene expression of ECM markers and BNP decreased in both groups; however, expression of TIMP-4 decreased only in group P (P=0.024). Conclusions— Mechanical unloading of the failing myocardium using pulsatile devices is more effective as indicated by echocardiographic parameters of systolic and diastolic LV function as well as dynamics of BNP and ECM markers. Therefore, specific effects of pulsatile mechanical unloading on the failing myocardium may have important implications for device selection especially for the purpose of bridge-to-recovery in patients with advanced HF.

An Open Label Dose Escalation Study to Evaluate the Safety of Administration of Non-Viral SDF-1 Plasmid to Treat Symptomatic Ischemic Heart Failure

Rationale: Preclinical studies indicate that adult stem cells induce tissue repair by activating endogenous stem cells through the stromal cell-derived factor-1:chemokine receptor type 4 axis. JVS-100 is a DNA plasmid encoding human stromal cell-derived factor-1. Objective: We tested in a phase 1, open-label, dose-escalation study with 12 months of follow-up in subjects with ischemic cardiomyopathy to see if JVS-100 improves clinical parameters. Methods and Results: Seventeen subjects with ischemic cardiomyopathy, New York Heart Association class III heart failure, with an ejection fraction ⩽40% on stable medical therapy, were enrolled to receive 5, 15, or 30 mg of JVS-100 via endomyocardial injection. The primary end points for safety and efficacy were at 1 and 4 months, respectively. The primary safety end point was a major adverse cardiac event. Efficacy end points were change in quality of life, New York Heart Association class, 6-minute walk distance, single photon emission computed tomography, N-terminal pro-brain natruretic peptide, and echocardiography at 4 and 12 months. The primary safety end point was met. At 4 months, all of the cohorts demonstrated improvements in 6-minute walk distance, quality of life, and New York Heart Association class. Subjects in the 15- and 30-mg dose groups exhibited improvements in 6-minute walk distance (15 mg: median [range]: 41 minutes [3–61 minutes]; 30 mg: 31 minutes [22–74 minutes]) and quality of life (15 mg: –16 points [+1 to –32 points]; 30 mg: –24 points [+17 to –38 points]) over baseline. At 12 months, improvements in symptoms were maintained. Conclusions: These data highlight the importance of defining the molecular mechanisms of stem cell-based tissue repair and suggest that overexpression of stromal cell-derived factor-1 via gene therapy is a strategy for improving heart failure symptoms in patients with ischemic cardiomyopathy.

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.

Liver dysfunction as a predictor of outcomes in patients with advanced heart failure requiring ventricular assist device support: Use of the Model of End-stage Liver Disease (MELD) and MELD eXcluding INR (MELD-XI) scoring system

BACKGROUND Liver dysfunction increases post-surgical morbidity and mortality. The Model of End-stage Liver Disease (MELD) estimates liver function but can be inaccurate in patients receiving oral anti-coagulation. We evaluated the effect of liver dysfunction on outcomes after ventricular assist device (VAD) implantation and the dynamic changes in liver dysfunction that occur during VAD support. METHODS We retrospectively analyzed 255 patients (147 with pulsatile devices and 108 with continuous-flow devices) who received a long-term VAD between 2000 and 2010. Liver dysfunction was estimated by MELD and MELD-eXcluding INR (MELD-XI), with patients grouped by a score of ≥ 17 or < 17. Primary outcomes were on-VAD, after transplant, and overall survival. RESULTS MELD and MELD-XI correlated highly (R ≥ 0.901, p < 0.0001) in patients not on oral anti-coagulation. Patients with MELD or MELD-XI < 17 had improved on-VAD and overall survival (p < 0.05) with a higher predictive power for MELD-XI. During VAD support, cholestasis initially worsened but eventually improved. Patients with pre-VAD liver dysfunction who survived to transplant had lower post-transplant survival (p = 0.0193). However, if MELD-XI normalized during VAD support, post-transplant survival improved and was similar to that of patients with low MELD-XI scores. CONCLUSIONS MELD-XI is a viable alternative for assessing liver dysfunction in heart failure patients on oral anti-coagulation. Liver dysfunction is associated with worse survival. However, if MELD-XI improves during VAD support, post-transplant survival is similar to those without prior liver dysfunction, suggesting an important prognostic role. We also found evidence of a transient cholestatic state after LVAD implantation that deserves further examination.

Hepatic dysfunction and survival after orthotopic heart transplantation: Application of the MELD scoring system for outcome prediction

BACKGROUND The prevalence of heart failure (HF) is rising and the only corrective treatment is cardiac transplantation. Advanced HF is associated with congestive hepatopathy and progressive functional and ultrastructural changes of the liver. We hypothesized that hepatic dysfunction is associated with impaired clinical outcome after heart transplantation. METHODS Data of 617 adult patients (75% men, mean age 53 ± 12 years, mean BMI 25 ± 4, mean ejection fraction 19 ± 9%) undergoing orthotopic heart transplantation (OHT) were analyzed retrospectively. Deviation from institutional normal ranges was used to define abnormal liver function. Standard Model for End-stage Liver Disease (MELD) scores were calculated and a modified MELD score with albumin replacing INR (modMELD) was created to eliminate the confounding effects of anti-coagulation. RESULTS Before OHT, AST, ALT and total bilirubin were elevated in 20%, 18% and 29% of the population, respectively. Total protein and albumin were decreased in 25% and 52% of the population, respectively. By 2 months post-transplantation, percentages of individuals with pathologic values decreased significantly, except for ALT, total protein and albumin, all of which took longer to normalize. Individuals with a higher pre-transplantation MELD or modMELD score had worse outcome 30 days post-transplant and reduced long-term survival over a 10-year follow-up. CONCLUSIONS In this large, single-center retrospective study, we demonstrated the dynamics of liver dysfunction after cardiac transplantation and that elevated MELD scores indicating impaired liver function are associated with poor clinical outcome after OHT. Thus, pre-operative liver dysfunction has a significant impact on survival of patients after cardiac transplantation.

Heart Transplantation in Human Immunodeficiency Virus–Positive Patients

BACKGROUND Human immunodeficiency virus (HIV) infection is widely considered a contraindication for cardiac transplantation. However, with the newer anti-retroviral drugs, the estimated 10-year survival after seroconversion is exceeds 90%. This case series describes the intermediate range outcome of HIV-positive cardiac transplant recipients. METHODS A retrospective analysis of 1679 cardiac transplant patients was undertaken to identify HIV-positive recipients. RESULTS Seven patients were identified. Five (4 men) were diagnosed with HIV before transplantation and 2 patients seroconverted after transplantation. Dilated cardiomyopathy was the indication for transplant in all patients. The 5 HIV recipients were aged 42 +/- 8 years, and time after HIV seroconversion averaged 9.5 years. All underwent cardiac transplantation as high-risk candidates. The CD4 count was 554 +/- 169 cells/microl, and viral load was undetectable in all patients at the time of transplantation. Two patients seroconverted to HIV-positive status at 1 and 7 years after transplant. No AIDS-defining illness was observed in any patient before or after transplant. Six patients received highly active anti-retroviral therapy. Viral load remained low in the presence of immunosuppression. All patients are alive with a follow-up from transplant of 57 +/- 78.9 months. CONCLUSION Excellent intermediate term outcome is noted in carefully selected HIV-positive patients. No significant AIDS-related infections or complications occurred.

Improved diabetic control in advanced heart failure patients treated with left ventricular assist devices.

Left ventricular assist devices (LVADs) are increasingly used as therapeutic options for patients with advanced congestive heart failure (CHF), many of whom suffer from diabetes mellitus (DM). The aim of this study was to evaluate the effect of restoration of normal cardiac output using LVAD support on diabetes control in patients with advanced CHF.

Left ventricular longitudinal strain by speckle-tracking echocardiography is associated with treatment-requiring cardiac allograft rejection.

BACKGROUND Noninvasive detection of rejection is a major objective in the management of heart transplant recipients. METHODS AND RESULTS To investigate the utility of 2-dimensional speckle-tracking echocardiography (2D-STE), we retrospectively evaluated 160 sets of endomyocardial biopsies and echocardiograms from 59 asymptomatic heart transplant recipients. Conventional International Society for Heart and Lung Transplantation grade 1B or higher rejection was considered as treatment-requiring rejection (group R), whereas International Society for Heart and Lung Transplantation grade 0 or 1A was classified as group Non-R. Left ventricular global longitudinal strain (GLS), global circumferential strain, and global radial strain were assessed by 2D-STE. Twenty-five specimens were classified into group R. GLS was significantly associated with treatment-requiring rejection, whereas neither global radial strain nor global circumferential strain were. Lower GLS remained significantly associated with an increased risk of treatment-requiring rejection (odds ratio, 1.15 [95% CI, 1.01-1.30]; P=0.03) even in multivariate analysis. GLS with the absolute value of less than 14.8% showed sensitivity and specificity of 64% and 63%, respectively, for detection of treatment-requiring rejection. CONCLUSION The 2D-STE-derived left ventricular GLS was associated with treatment-requiring rejection. Two-dimensional STE might be useful as a noninvasive supplemental tool for monitoring heart transplant recipients for possible treatment-requiring rejection.

Risk stratification of ambulatory patients with advanced heart failure undergoing evaluation for heart transplantation.

BACKGROUND Risk stratification of ambulatory heart failure (HF) patients has relied on peak VO(2)<14 ml/kg/min. We investigated whether additional clinical variables might further specify risk of death, ventricular assist device (VAD) implantation (INTERMACS <4) or heart transplantation (HTx, Status 1A or 1B) within 1 year after HTx evaluation. We hypothesized that right ventricular stroke work index (RVSWI), pulmonary capillary wedge pressure (PCWP) and the model for end-stage liver disease-albumin score (MELD-A) would be additive prognostic predictors. METHODS We retrospectively collected data on 151 ambulatory patients undergoing HTx evaluation. Primary outcomes were defined as HTx, LVAD or death within 1 year after evaluation. RESULTS Average age in our cohort was 55 ± 11.1 years, 79.1% were male and 39% had an ischemic etiology (LVEF 21 ± 10.5% and peak VO(2) 12.6 ± 3.5 ml/kg/min). Fifty outcomes (33.1%) were observed (27 HTxs, 15 VADs and 8 deaths). Univariate logistic regression showed a significant association of RVSWI (OR 0.47, p = 0.036), PCWP (OR 2.65, p = 0.007) and MELD-A (OR 2.73, p = 0.006) with 1-year events. Stepwise regression showed an independent correlation of RVSWI<5gm-m(2)/beat (OR 6.70, p < 0.01), PCWP>20 mm Hg (OR 5.48, p < 0.01), MELD-A>14 (OR 3.72, p< 0.01) and peak VO(2)<14 ml/kg/min (OR 3.36, p = 0.024) with 1-year events. A scoring system was developed: MELD-A>14 and peak VO(2)<14-1 point each; and PCWP>20 and RVSWI<5-2 points each. A cut-off at≥4 demonstrated a 54% sensitivity and 88% specificity for 1-year events. CONCLUSIONS Ambulatory HF patients have significant 1-year event rates. Risk stratification based on exercise performance, left-sided congestion, right ventricular dysfunction and liver congestion allows prediction of 1-year prognosis. Our findings support early and timely referral for VAD and/or transplant.