Joseph D. Mishkin

Relationship of Right- to Left-Sided Ventricular Filling Pressures in Advanced Heart Failure Insights From the ESCAPE Trial

Background—Although right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP) are correlated in heart failure, in a sizeable minority of patients, the RAP and PCWP are not tightly coupled. The basis of this variability in the RAP/PCWP ratio, and whether it conveys prognostic value, is not known. Methods and Results—We analyzed the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial database. Baseline characteristics, including echocardiographic assessment of right ventricular (RV) structure and function, and invasively measured hemodynamic parameters, were compared among tertiles of the RAP/PCWP ratio. Multivariable Cox proportional hazard models assessed the association of RAP/PCWP ratio with the primary ESCAPE outcome (6-month death or hospitalization [days]) adjusting for systolic blood pressure, blood urea nitrogen, 6-minute walk distance, and PCWP. The RAP/PCWP tertiles were 0.27 to 0.4 (tertile 1); 0.41 to 0.615 (tertile 2), and 0.62 to 1.21 (tertile 3). Increasing RAP/PCWP was associated with increasing median right atrial area (23, 26, 29 cm2, respectively; P<0.005), RV area in diastole (21, 27, 27 cm2, respectively; P<0.005), and pulmonary vascular resistance (2.4, 2.9, 3.6 woods units, respectively; P=0.003), and lower RV stroke work index (8.6, 8.4, 5.5 g·m/m2 per beat, respectively; P<0.001). RAP/PCWP ratio was associated with death or hospitalization within 6 months (hazard ratio, 1.16 [1, 1.4]; P<0.05). Conclusions—Increased RAP/PCWP ratio was associated with higher pulmonary vascular resistance, reduced RV function (manifest as a larger right atrium and ventricle and lower RV stroke work index), and an increased risk of adverse outcomes in patients with advanced heart failure.

Utilization of Cardiac Computed Tomography Angiography for the Diagnosis of Left Ventricular Assist Device Thrombosis

The use of left ventricular assist devices (LVADs) in the management of advanced heart failure has grown substantially in recent years, with implantation of these devices increasing 10-fold since the approval of a continuous-flow device for destination therapy in January 2010. With the significant increase in use of this technology comes the potential for an increased incidence of complications associated with these devices. One such complication that can be fatal if not urgently recognized is device thrombosis, which has been reported to occur in approximately 1% of patients receiving the HeartMate II LVAD.1 Cardiologists, radiologists, and other health care professionals must become increasingly more adept …

High-Sensitivity Cardiac Troponin I Assay to Screen for Acute Rejection in Patients With Heart Transplant

Background—A noninvasive biomarker that could accurately diagnose acute rejection (AR) in heart transplant recipients could obviate the need for surveillance endomyocardial biopsies. We assessed the performance metrics of a novel high-sensitivity cardiac troponin I (cTnI) assay for this purpose. Methods and Results—Stored serum samples were retrospectively matched to endomyocardial biopsies in 98 cardiac transplant recipients, who survived ≥3 months after transplant. AR was defined as International Society for Heart and Lung Transplantation grade 2R or higher cellular rejection, acellular rejection, or allograft dysfunction of uncertain pathogenesis, leading to treatment for presumed rejection. cTnI was measured with a high-sensitivity assay (Abbott Diagnostics, Abbott Park, IL). Cross-sectional analyses determined the association of cTnI concentrations with rejection and International Society for Heart and Lung Transplantation grade and the performance metrics of cTnI for the detection of AR. Among 98 subjects, 37% had ≥1 rejection episode. cTnI was measured in 418 serum samples, including 35 paired to a rejection episode. cTnI concentrations were significantly higher in rejection versus nonrejection samples (median, 57.1 versus 10.2 ng/L; P<0.0001) and increased in a graded manner with higher biopsy scores (Ptrend<0.0001). The c-statistic to discriminate AR was 0.82 (95% confidence interval, 0.76–0.88). Using a cut point of 15 ng/L, sensitivity was 94%, specificity 60%, positive predictive value 18%, and negative predictive value 99%. Conclusions—A high-sensitivity cTnI assay seems useful to rule out AR in cardiac transplant recipients. If validated in prospective studies, a strategy of serial monitoring with a high-sensitivity cTnI assay may offer a low-cost noninvasive strategy for rejection surveillance.

Association of cardiac troponin i with disease severity and outcomes in patients with pulmonary hypertension

Previous studies have identified cardiac troponin I (cTnI) as an important marker in pulmonary hypertension (PH) prognosis. However, traditional assays are limited by poor sensitivity, even among patients at high risk. cTnI was measured in 255 PH patients using a new highly sensitive (hs) assay. Other measures included demographics, creatinine, 6-minute walk distance, hemodynamics, cardiac magnetic resonance imaging, and B-type natriuretic peptide level. The association between cTnI and survival was assessed using Kaplan-Meier analysis and Cox regression. cTnI was detectable with the hs assay in 95% of the patients with a median level of 6.9 pg/ml (IQR 2.7-12.6 pg/ml). Higher cTnI levels associated with higher levels of B-type natriuretic peptide, shorter 6-minute walk distance, and more severe hemodynamic and cardiac magnetic resonance imaging abnormalities. During a median follow-up of 3.5 years, 60 individuals died. Unadjusted event rates increased across higher cTnI quartiles (3, 5, 13, 17 events/100 person-years, respectively, p trend = 0.002). cTnI in the fourth (vs first) quartile remained associated with death in a final stepwise multivariable model that included clinical variables and hemodynamics (adjusted hazard ratio 5.3, 95% confidence interval 1.8-15.6). In conclusion, cTnI levels, detectable with a novel hs assay, identify patients with PH who have more severe hemodynamic and cardiac structural abnormalities and provide novel and independent prognostic information. This hs assay has the potential to detect more at-risk patients and improve current risk-stratification algorithms.

Relationship of Right- to Left-Sided Ventricular Filling Pressures in Advanced Heart FailureClinical Perspective

Background—Although right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP) are correlated in heart failure, in a sizeable minority of patients, the RAP and PCWP are not tightly coupled. The basis of this variability in the RAP/PCWP ratio, and whether it conveys prognostic value, is not known. Methods and Results—We analyzed the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial database. Baseline characteristics, including echocardiographic assessment of right ventricular (RV) structure and function, and invasively measured hemodynamic parameters, were compared among tertiles of the RAP/PCWP ratio. Multivariable Cox proportional hazard models assessed the association of RAP/PCWP ratio with the primary ESCAPE outcome (6-month death or hospitalization [days]) adjusting for systolic blood pressure, blood urea nitrogen, 6-minute walk distance, and PCWP. The RAP/PCWP tertiles were 0.27 to 0.4 (tertile 1); 0.41 to 0.615 (tertile 2), and 0.62 to 1.21 (tertile 3). Increasing RAP/PCWP was associated with increasing median right atrial area (23, 26, 29 cm2, respectively; P<0.005), RV area in diastole (21, 27, 27 cm2, respectively; P<0.005), and pulmonary vascular resistance (2.4, 2.9, 3.6 woods units, respectively; P=0.003), and lower RV stroke work index (8.6, 8.4, 5.5 g·m/m2 per beat, respectively; P<0.001). RAP/PCWP ratio was associated with death or hospitalization within 6 months (hazard ratio, 1.16 [1, 1.4]; P<0.05). Conclusions—Increased RAP/PCWP ratio was associated with higher pulmonary vascular resistance, reduced RV function (manifest as a larger right atrium and ventricle and lower RV stroke work index), and an increased risk of adverse outcomes in patients with advanced heart failure.

A Sensitive Cardiac Troponin I Assay to Screen for Acute Rejection in Heart Transplant Patients

Background—A noninvasive biomarker that could accurately diagnose acute rejection (AR) in heart transplant recipients could obviate the need for surveillance endomyocardial biopsies. We assessed the performance metrics of a novel high-sensitivity cardiac troponin I (cTnI) assay for this purpose. Methods and Results—Stored serum samples were retrospectively matched to endomyocardial biopsies in 98 cardiac transplant recipients, who survived ≥3 months after transplant. AR was defined as International Society for Heart and Lung Transplantation grade 2R or higher cellular rejection, acellular rejection, or allograft dysfunction of uncertain pathogenesis, leading to treatment for presumed rejection. cTnI was measured with a high-sensitivity assay (Abbott Diagnostics, Abbott Park, IL). Cross-sectional analyses determined the association of cTnI concentrations with rejection and International Society for Heart and Lung Transplantation grade and the performance metrics of cTnI for the detection of AR. Among 98 subjects, 37% had ≥1 rejection episode. cTnI was measured in 418 serum samples, including 35 paired to a rejection episode. cTnI concentrations were significantly higher in rejection versus nonrejection samples (median, 57.1 versus 10.2 ng/L; P<0.0001) and increased in a graded manner with higher biopsy scores (Ptrend<0.0001). The c-statistic to discriminate AR was 0.82 (95% confidence interval, 0.76–0.88). Using a cut point of 15 ng/L, sensitivity was 94%, specificity 60%, positive predictive value 18%, and negative predictive value 99%. Conclusions—A high-sensitivity cTnI assay seems useful to rule out AR in cardiac transplant recipients. If validated in prospective studies, a strategy of serial monitoring with a high-sensitivity cTnI assay may offer a low-cost noninvasive strategy for rejection surveillance.

Sirolimus use and incidence of venous thromboembolism in cardiac transplant recipients

Sirolimus is an immunosuppressive agent increasingly used in cardiac transplant recipients in the setting of allograft vasculopathy or worsening renal function. Recently, sirolimus has been associated with increased risk of venous thromboembolism (VTE) in lung transplant recipients. To investigate whether this association is also present in cardiac transplant recipients, we retrospectively reviewed the charts of 67 cardiac transplant recipients whose immunosuppressive regimen included sirolimus and 134 matched cardiac transplant recipients whose regimen did not include sirolimus. Rates of VTE were compared. Multivariable Cox proportional hazards models tested the association of sirolimus use with VTE. A higher incidence of VTE was seen in patients treated with vs. without sirolimus (8/67 [12%] vs. 9/134 [7%], log‐rank statistic: 4.66, p = 0.03). Lower body mass index (BMI) and total cholesterol levels were also associated with VTE (p < 0.05). The association of sirolimus with VTE persisted when adjusting for BMI (hazard ratio [95% confidence interval]: 2.96 [1.13, 7.75], p = 0.03) but not when adjusting for total cholesterol (p = 0.08). These data suggest that sirolimus is associated with an increased risk of VTE in cardiac transplant recipients, a risk possibly mediated through comorbid conditions. Larger, more conclusive studies are needed. Until such studies are completed, a heightened level of awareness for VTE in cardiac transplant recipients treated with sirolimus appears warranted.

Concentric left ventricular hypertrophy as assessed by cardiac magnetic resonance imaging and risk of death in cardiac transplant recipients

BACKGROUND Although risk factors for left ventricular (LV) hypertrophy in the native heart are well known, as is its association with increased risk of adverse outcomes, such information is poorly defined in heart transplant (HTx) recipients. We determined whether increased LV mass and concentricity (mass/volume) were associated with death in patients after HTx. METHODS Between May 2003 and May 2006, 140 HTx recipients underwent cardiac magnetic resonance imaging (MRI). Clinical characteristics associated with increased LV mass were determined. Cox proportional hazard models were constructed to assess the relationship of LV mass and concentricity with death. RESULTS MRIs were acquired a median of 6.0 years after transplant. The top quartile of indexed LV mass and concentricity were 35.8 g/m(2.7) or higher and 1.5 g/ml or higher, respectively. History of rejection (odds ratio [OR], 5.9; 95% confidence interval [CI], 2.1-16.4; p < 0.01), diabetes (OR, 3.3; 95% CI, 1.3-8.2; p = 0.01), and post-transplant year of MRI acquisition (OR, 1.2; 95% CI, 1.1-1.4; p < 0.01) were associated with the top quartile of LV mass in multivariable models. LV mass and concentricity were independently associated with cardiovascular death (hazard risk [HR], 1.11 per g/m;(2.7) HR, 10.1 per g/ml, p ≤ 0.01, respectively). LV concentricity was independently associated with all-cause mortality (HR, 4.4 per g/ml, p < 0.01). CONCLUSION A history of rejection and diabetes are associated with increased LV mass. Increased LV mass, particularly of a concentric phenotype, is an independent risk factor for cardiovascular and all-cause mortality after HTx.

Health insurance as a requirement to undergo cardiac transplantation: A national survey of transplant program practices

BACKGROUND Recent limitations in Medicaid coverage of transplantation in Arizona jeopardized transplantation of potential recipients in that state and called attention to financial barriers inherent in the present organ allocation system. Policies of cardiac transplant centers regarding insurance requirements for transplantation have not been previously assessed. We sought to determine the policies of adult cardiac transplant programs nationwide regarding insurance requirements for evaluation and listing for cardiac transplantation. METHODS From December 15, 2008 to November 16, 2010, all active adult cardiac transplant programs in the United States were surveyed regarding insurance requirements for evaluation and listing for cardiac transplantation. RESULTS Surveys were completed by 62 of 101 programs, accounting for 71% of adult cardiac transplants in 2007. Only 2% of recipients were uninsured. Insurance was required by 48% of programs to evaluate and 84% to list for transplantation. For uninsured patients, 81% of programs required a large amount of money upfront (median,

Successful Use of the TandemHeart Percutaneous Ventricular Assist Device as a Bridge to Recovery for Acute Cellular Rejection in a Cardiac Transplant Patient

200,000; interquartile range,