Samit S. Roy

Derivation and High Engraftment of Patient-Specific Cardiomyocyte-Sheet Using Induced Pluripotent Stem Cells Generated From Adult Cardiac Fibroblast

Background—Induced pluripotent stem cells (iPSCs) can be differentiated into potentially unlimited lineages of cell types for use in autologous cell therapy. However, the efficiency of the differentiation procedure and subsequent function of the iPSC-derived cells may be influenced by epigenetic factors that the iPSCs retain from their tissues of origin; thus, iPSC-derived cells may be more effective for treatment of myocardial injury if the iPSCs were engineered from cardiac-lineage cells, rather than dermal fibroblasts. Methods and Results—We show that human cardiac iPSCs (hciPSCs) can be generated from cardiac fibroblasts and subsequently differentiated into exceptionally pure (>92%) sheets of cardiomyocytes (CMs). The hciPSCs passed through all the normal stages of differentiation before assuming a CM identity. When using the fibrin gel–enhanced delivery of hciPSC-CM sheets at the site of injury in infarcted mouse hearts, the engraftment rate was 31.91%±5.75% at Day 28 post transplantation. The hciPSC-CM in the sheet also appeared to develop a more mature, structurally aligned phenotype 28 days after transplantation and was associated with significant improvements in cardiac function, vascularity, and reduction in apoptosis. Conclusions—These data strongly support the potential of hciPSC-CM sheet transplantation for the treatment of heart with acute myocardial infarction.

Anti-factor Xa and activated partial thromboplastin time measurements for heparin monitoring in mechanical circulatory support.

OBJECTIVES This study investigated the relationship between anti-factor Xa (anti-FXa) and activated partial thromboplastin time (aPTT) for monitoring intravenous unfractionated heparin (IV-UFH) in patients with continuous-flow left ventricular assist devices (CF-LVADs). BACKGROUND CF-LVADs have become mainstream therapy for patients with advanced heart failure. Thromboembolic events, device thrombosis, and bleeding continue to be a challenge with this technology. Adequate anticoagulation is required to prevent these adverse events. METHODS A prospective study of consecutive patients implanted with a CF-LVAD was conducted. Paired samples were considered concordant if aPTT values fell into expected ranges for subtherapeutic, therapeutic, and supratherapeutic anti-FXa levels. Heparin dosing was on the basis of anti-Xa levels. RESULTS A total of 340 paired values from 38 patients were evaluated. Anti-FXa and aPTT were discordant in 253 samples (74.4%), with a high degree of variability in aPTT for any given anti-FXa level (r(2) = 0.57). Results were discordant in 104 samples (63.8%) from patients undergoing bridging therapy with warfarin and in 149 samples (84.2%) from patients with device obstruction and/or hemolysis (p < 0.001). The most common pattern of discordance was a supratherapeutic aPTT value despite a therapeutic anti-FXa level (49.1% for bridging vs. 75.8% for device obstruction and/or hemolysis; p < 0.001). CONCLUSIONS Levels of aPTT were disproportionately prolonged relative to the corresponding anti-FXa levels in CF-LVAD patients, particularly those with device obstruction. Hemolysis and warfarin administration may falsely elevate aPTT, resulting in overestimation of heparin concentration and under-anticoagulation. Use of aPTT and anti-FXa to guide heparin therapy may lead to different estimates of heparin concentration in the same patient.

Echocardiographic Ramp Test for Continuous-Flow Left Ventricular Assist Devices : Do Loading Conditions Matter?

OBJECTIVES This study investigated whether continuous AI and/or elevated mean arterial pressure (MAP) were associated with false positive results for flow obstruction in echocardiographic ramp speed tests in patients with a continuous-flow left ventricular assist device. BACKGROUND Failure to reduce the left ventricular end-diastolic diameter (LVEDD) with increasing device speeds in a ramp test is predictive of pump obstruction. Aortic insufficiency (AI) or increased MAP can diminish the ability to unload the left ventricle. METHODS LVEDD was plotted against device speed, and a linear function slope was calculated. A flat LVEDD slope (≥-0.16) was considered abnormal (suggestive of obstruction). Ramp test results were compared in patients with or without either AI or increased MAP at baseline speed, and receiver-operator characteristic (ROC) curves were constructed for predictors of device obstruction. Device thrombosis was confirmed by direct visualization of clot at explantation or on inspection by the manufacturer. RESULTS Of 78 ramp tests (55 patients), 36 were abnormal (18 true positive, 18 false positive), and 42 were normal (37 true negative, 5 false negative). In patients with AI, LVEDD slope was -0.14 ± 0.17, which was consistent with device obstruction (vs. -0.25 ± 0.11 in patients without AI; p < 0.001), despite no difference in mean lactate dehydrogenase concentration between the 2 groups (1,301 ± 1,651 U/l vs. 1,354 ± 1,365 U/l; p = 0.91). Area under the ROC curve (AUC) for LVEDD slope was 0.76 and improved to 0.88 after removal of patients with AI from the study. LVEDD slope in patients with MAP ≥85 mm Hg was similar to that for device obstruction (-0.18 ± 0.07) and was abnormal in 6 of the 12 ramp tests performed. Combining LVEDD slope with lactate dehydrogenase concentration increased the AUC to 0.96 as an indicator of device obstruction. CONCLUSIONS Abnormal loading conditions due to AI or elevated MAP may result in false positive ramp tests.

Trends and Outcomes of Pulmonary Arterial Hypertension–Related Hospitalizations in the United States: Analysis of the Nationwide Inpatient Sample Database From 2001 Through 2012

Importance Recent trends and outcomes of pulmonary arterial hypertension (PAH)-related hospitalization in adults in the United States are unknown. Objective To examine the characteristics of PAH-related hospitalizations. Design, Setting, and Participants We analyzed the National Inpatient Sample database for all adult patients (≥18 years old) with PAH as the principal discharge diagnosis from January 1, 2001, through December 31, 2012. Main Outcomes and Measures We analyzed the temporal trends in hospitalization rate, hospital charges, in-hospital mortality, length of hospitalization, and comorbidities pertaining to PAH-related hospitalizations. We also evaluated the predictors of in-hospital mortality and length of hospitalizations. Results The number of PAH-related hospitalizations per year in adults decreased significantly from 2001 through 2012 (3177 vs 1345, P for trend <.001). However, the mean hospital charge per admission increased 2.7-fold from 2001 through 2012 (

β-Blocker Therapy Is Not Associated With Adverse Outcomes in Patients With Pulmonary Arterial Hypertension A Propensity Score Analysis

29 507 vs

Gastrointestinal Bleeding during Continuous-Flow Left Ventricular Assist Device Support is Associated with Lower Rates of Cardiac Transplantation.

79 607, P for trend <.001). There was a significant increase in each of these associated comorbid conditions: diabetes (4.6%-7.8%), hypertension (5.1%-17.1%), coronary artery disease (15.6%-22.3%), chronic obstructive pulmonary disease (14.4%-20.1%), anemia (12.4%-20.4%), cardiac dysrhythmias (21.7%-29.0%), congestive heart failure (40.7%-56.1%), acute (5.9%-20.1%) or chronic kidney disease (1.1%-16.4%), fluid and electrolyte imbalance (18.9%-35.3%), pneumonia (4.4%-6.3%), cardiogenic shock (0.5%-1.5%), and acute respiratory failure (4.3%-20.8%) from 2001 through 2012. The length of hospitalization increased (mean [SE], 7.0 [0.5] days in 2001 vs 7.6 [0.6] days in 2012, P for trend = .009), but in-patient mortality remained unchanged (7.8% [1.1%] in 2001 vs 6.3% [1.7%] in 2012, P for trend = .54). Admission to a teaching hospital (β coefficient for length of hospitalization, 2.0; 95% CI, 1.3-1.6; odds ratio [OR] for mortality, 1.5; 95% CI, 1.1-2.1), cardiac dysrhythmias (β coefficient, 1.8; 95% CI, 1.1-2.6; OR, 1.8; 95% CI, 1.4-2.4), acute kidney injury (β coefficient, 5.0; 95% CI, 3.9-6.1; OR, 2.3; 95% CI, 1.7-3.2), acute cerebrovascular accident (β coefficient, 6.6; 95% CI, 1.9-11.3; OR, 6.7; 95% CI, 2.1-21.1), and acute respiratory failure (β coefficient, 6.2; 95% CI, 5.1-7.4; OR, 5.6; 95% CI, 4.2-7.5) were associated with increased length of hospitalization and in-hospital mortality. Congestive heart failure (OR, 1.7; 95% CI, 1.3-2.2), cardiogenic shock (OR, 5.4; 95% CI, 2.7-10.9), and fluid and electrolyte imbalance (OR, 1.9; 95% CI, 1.5-2.4) were associated with increased in-hospital mortality but not length of hospitalization. Conclusions and Relevance Analyses of temporal changes in PAH care reveal a significant decrease in PAH-related hospitalizations in the United States, but hospital charges have increased substantially and are increasingly being borne by Medicare. In-hospital mortality remains unchanged, but length of hospitalization has increased. This study should help identify the characteristics of patients with PAH that are associated with increased risk of in-hospital mortality and longer length of hospitalization.

The Contribution of Tobacco Use to High Health Care Utilization and Medical Costs in Peripheral Artery Disease: A State-Based Cohort Analysis

Background—The safety of &bgr;-blockers in patients with isolated right ventricular failure because of pulmonary arterial hypertension (PAH) is unclear. Methods and Results—We studied 564 PAH patients (total cohort) referred to our center from 1982 to 2013. Propensity score-matching was used to match pairs of PAH patients with and without &bgr;-blocker use (matched cohort). We compared all-cause mortality between the groups in the total cohort and the matched cohort using bootstrap validation, Kaplan–Meier, and Cox proportional hazard analyses. Seventy-one of the 564 patients in the total cohort were on &bgr;-blockers. They were older, had higher prevalence of comorbidities, and were more often on diuretics, digoxin, and angiotensin converting enzyme inhibitors. The severity of PAH and right ventricular failure was similar between those with and without &bgr;-blocker use. After propensity matching, 63 patients with &bgr;-blocker use were compared with 51 patients without &bgr;-blocker use. During a median follow-up time of 4.8 years, there were 339 (60%) deaths in the total cohort and 70 deaths (61%) in the matched cohort. There was no difference in absolute mortality between those with and without &bgr;-blockers (P=0.71). &bgr;-Blocker use was not associated with increased all-cause mortality in the total cohort after adjusting for propensity score (adjusted hazard ratio, 1.0; 95% confidence interval, 0.7–1.5) and in the matched cohort (hazard ratio, 1.2; 95% confidence interval, 0.8–2.0). Conclusions—There was no statistically significant difference in long-term mortality between propensity score-matched pairs of PAH patients with and without &bgr;-blocker use. These findings need further validation in prospective clinical trials.

β-Blocker Therapy Is Not Associated With Adverse Outcomes in Patients With Pulmonary Arterial HypertensionCLINICAL PERSPECTIVE

Gastrointestinal bleeding (GIB) remains a significant problem after continuous-flow left ventricular assist device (CF-LVAD) implantation. We hypothesized that the subsequent need for blood transfusions in patients with GIB may reduce rates of cardiac transplantation. We performed a retrospective review of 232 patients implanted with the HeartMate II (HM II) CF-LVAD from June 2005 through May 2013 at our center to determine risk factors for GIB and assess its effect on cardiac transplantation. Over a total LVAD follow-up time of 364 person-years, 62 GIB episodes occurred in 49 patients (27%), for an event rate of 0.45 gastrointestinal bleeds/patient-year of LVAD support. Women made up 15% of our cohort, yet contributed 29% of the GIB (p = 0.06). Survival at 6 month, 1 year, and 2 years was not statistically different in patients who developed GIB and those who did not (77% vs 78%, 74% vs 71%, and 61% vs 54%, respectively). In transplant-eligible patients, GIB was associated with a 27% lower rate of cardiac transplantation (rate ratio 0.73, p < 0.05). Although the mechanism behind this finding is unclear, GIB appears to be linked to higher transfusion rates, which may cause the development of subsequent allosensitization.

Beta-Blocker Therapy Is Not Associated With Adverse Outcomes in Patients With Pulmonary Arterial Hypertension: A Propensity Score Analysis

BACKGROUND Tobacco use is an important preventable cause of peripheral artery disease (PAD) and a major determinant of adverse clinical outcomes. OBJECTIVES This study hypothesized that tobacco use by PAD patients would be associated with higher health care utilization and associated costs. METHODS We conducted a retrospective, cross-sectional study using 2011 claims data from the largest Minnesota health plan. The total cohort included individuals with 12 months of continuous enrollment and ≥ 1 PAD-related claim. Tobacco cessation pharmacotherapy billing codes were queried in a subgroup with pharmacy benefits. Outcomes were total costs, annual proportion of members hospitalized, and primary discharge diagnoses. RESULTS A PAD cohort of 22,203 was identified, comprising 1,995 (9.0%) tobacco users. A subgroup of 9,027 with pharmacy benefits included 1,158 (12.8%) tobacco users. The total cohort experienced 22,220 admissions. The pharmacy benefits subgroup experienced 8,152 admissions. Within 1 year, nearly one-half the PAD tobacco users were hospitalized, 35% higher than nonusers in the total cohort (p < 0.001) and 30% higher in the subgroup (p < 0.001). In both cohorts, users were more frequently admitted for peripheral or visceral atherosclerosis (p < 0.001), acute myocardial infarction (p < 0.001), and coronary heart disease (p < 0.05). Observed costs in the total cohort were

Safety and Outcomes of Capsule Endoscopy in Patients with Left Ventricular Assist Device: a Single-Center Retrospective Case Series.

64,041 for tobacco users versus