Inhaled nitric oxide improves exercise capacity in patients with severe heart failure and right ventricular dysfunction.

Fourteen cardiac transplant candidates were studied with cardiopulmonary exercise testing at baseline and while breathing nitric oxide (40 ppm). Oxygen consumption at the anaerobic threshold was improved by breathing nitric oxide in patients with pulmonary hypertension and in patients with an elevated left ventricular end-diastolic volume index.

Sex and left ventricular volume predict survival in heart transplant candidates with peak oxygen uptake between ten and fourteen milliliters per kilogram per minute.

BACKGROUND: The purpose of this study was to identify predictors of survival in patients referred for heart transplantation evaluation who had a peak oxygen uptake of 10 to 14 ml/kg/min measured during initial cardiopulmonary exercise testing. METHODS: Seventy-two patients were identified retrospectively from a database of 304 patients who underwent heart transplantation evaluations at our center from 1985 to 1995. All 72 patients underwent right-sided heart catheterization and first-pass right and left ventricular radionuclide ventriculography during cardiopulmonary exercise testing. RESULTS: There were 14 women and 58 men in the study (mean age 52 +/- 9 years, 80% male, 79% New York Heart Association class III/IV, left ventricular ejection fraction of 0.24 +/- 0.9, and left ventricular end-diastolic volume index of 144 +/- 59 ml). During a mean follow-up of 19 +/- 23 months, two women and 32 men (47%) reached the combined end point of death (n = 20) or pretransplantation admission for inotropic or mechanical support (n = 14). For the entire cohort, analysis of clinical, ventriculographic, and exercise parameters identified female sex, younger age, and age/ sex-adjusted peak oxygen uptake as independent predictors of survival. In men only, age, left ventricular end-diastolic volume index, and age/sex adjusted peak oxygen uptake were independent predictors of survival. CONCLUSIONS: Among patients referred for heart transplantation evaluation with a peak oxygen uptake between 10 to 14 ml/kg/min, younger age, female sex, and higher age/ sex-adjusted peak oxygen uptake predict longer survival to the combined end point of death or pretransplantation admission for inotropic or mechanical support. These measures may be useful in additional risk stratification of such patients.

Local relation between oxidative metabolism and perfusion in leg muscles of patients with heart failure studied by magnetic resonance imaging and spectroscopy.

BACKGROUND: We studied the local relation of muscle perfusion and metabolism in patients with severe chronic heart failure. Alterations of skeletal muscle blood flow and oxidative capacity contribute to exercise intolerance in these patients. The interdependence of both parameters has often been questioned. METHODS AND RESULTS: With the use of nuclear magnetic resonance, we quantified leg and muscle perfusion during reactive hyperemia in 7 patients with heart failure (New York Heart Association class III and IV) and 7 age-matched control subjects from the difference in longitudinal relaxation rate (1/T1). By using 31P nuclear magnetic resonance spectroscopy, we assessed oxidative metabolism from the creatine rephosphorylation time constant after a short ischemic exercise. Phosphocreatine recovery is slowed (74.6 +/- 11.3 vs 49.9 +/- 13.9 seconds, p = .002) and reactive hyperemic flow is reduced (48.5 +/- 24.9 vs 113 +/- 30.4 mL/100 mL per minute, p = .0005). CONCLUSIONS: By using a totally noninvasive protocol, we demonstrated that reactive hyperemic flow correlates with oxidative capacity in calf muscles from patients with heart failure, showing that exercise performance and local circulatory dysfunction are decreased in parallel in severe heart failure.

Left ventricular end-diastolic volume index, age, and maximum heart rate at peak exercise predict survival in patients referred for heart transplantation.

BACKGROUND: This study sought to define clinical predictors of survival in patients under consideration for heart transplantation and demonstrate possible improvements in the prediction of outcome when considering the identified predictors in addition to peak oxygen consumption. Peak oxygen consumption is currently the most important criterion for determining the timing and appropriateness of heart transplantation in ambulatory patients. METHODS: To identify other possible predictors of survival in patients with heart failure, we reviewed clinical, exercise, and radionuclide ventriculographic data on 112 patients referred for heart transplantation evaluation. Predictors of 1-year (n = 86) and overall (n = 112) survival to the combined end point of freedom from death or pretransplantation admission for inotropic or mechanical support were identified in multivariate analysis. RESULTS: The mean age was 51+/-9 years, and the mean duration of follow-up was 408+/-366 days. The mean left ventricular ejection fraction was 0.22+/-0.07, and the mean peak oxygen consumption was 12.3+/-3.7 ml/min/kg. Age (odds ratio 1.087, 95% confidence interval [CI] 1.021 to 1.157), percentage of the maximum predicted heart rate at peak exercise (odds ratio 0.958, 95% CI 0.924 to 0.992), and left ventricular end-diastolic volume index (odds ratio 1.019, 95% CI 1.006 to 1.033) were independent predictors of the 1-year combined end point. CONCLUSION: Age, heart rate at peak exercise, and left ventricular end-diastolic volume index are independent predictors of prognosis in patients with advanced heart failure and may provide additional prognostic information for the risk-stratification of potential heart transplant recipients.

Successful long-term use of sitagliptin for the treatment of new-onset diabetes mellitus after solid organ transplantation: a case report.

AIMS: To describe 2.5 years of exposure to sitagliptin on glycemic control, immunosuppressive therapy, and adverse events following solid organ transplantation. CASE REPORT: A 63-year-old Caucasian male received an orthotopic heart transplantation in June of 2006 secondary to idiopathic nonischemic cardiomyopathy. He was diagnosed with new-onset diabetes mellitus after transplantation (NODAT). Sitagliptin monotherapy was initiated in August 2007 and continued for 2.5 years. RESULTS: Hemoglobin A(1c) increased from 5.8% to 6.1%, but the recommended glycemic target of <7% was maintained over time and improvements in fasting home blood glucose monitoring values were achieved. Tacrolimus concentrations were not altered. Only minor dose adjustments to tacrolimus and mycophenolate mofetil were required. Maintenance corticosteroid dose remained unchanged and there was no evidence of biopsy-proven acute rejection. No adverse events were reported. DISCUSSION: This case report demonstrates that long-term sitagliptin treatment for NODAT may be effective, safe, and well tolerated in solid organ transplant recipients.

Development and characterization of a cyclophosphamide-resistant subline of acute myeloid leukemia in the Lewis x Brown Norway hybrid rat.

Preclinical studies of resistance to alkylating agents in the Lewis x Brown Norway hybrid (LBN) rat model of acute myeloid leukemia (AML) have hitherto been limited by the sensitivity of LBN AML cells to cyclophosphamide (CY). We developed a CY-resistant subline of LBN AML by serial intravenous (IV) passage of AML cells followed by in vivo exposure to CY (100 mg/kg) 14 days later. After 18 and subsequent passages, CY-treated AML cells remained viable despite ex vivo incubation with 70 to 100 mumol/L 4-hydroperoxycyclophosphamide (4HC) or in vivo exposure to 100 to 300 mg/kg of CY. Once established, resistance to incubation with 4HC was stable in LBN AML cells after at least six serial in vivo passages without exposure to CY. Nevertheless, both control and CY-treated AML cells demonstrated similar dose-dependent sensitivity to 100 to 500 mumol/L phosphoramide mustard (PhM), the active alkylating end-product of CY activation in vivo. Levels of aldehyde dehydrogenase (ALDH), which inactivates CY by prevention of formation of PhM, were significantly elevated in these CY-resistant AML cells: cytosolic and particulate ALDH fractions from these cells were 11 to 13 times control with NAD cofactor and propanal substrate and three to four times control with NADP cofactor and benzaldehyde substrate. Further studies with this animal model of AML, in which resistance to CY is mediated by elevated ALDH activity, may elucidate mechanisms for effective elimination of drug-resistant leukemic cells ex vivo and in vivo.

Measurement of human myocardial perfusion by double-gated flow alternating inversion recovery EPI.

This paper presents a flow-sensitive alternating inversion recovery (FAIR) method for measuring human myocardial perfusion at 1.5 T. Slice-selective/non-selective IR images were collected using a double-gated IR echoplanar imaging sequence. Myocardial perfusion was calculated after T1 fitting and extrapolation of the mean signal difference SI(Sel - SI(NSel). The accuracy of the method was tested in a porcine model using graded intravenous adenosine dose challenge. Comparison with radiolabeled microsphere measurements showed a good correlation (r = 0.84; mean error = 20%, n = 6) over the range of flows tested (0.9-7 ml/g/min). Applied in humans, this method allowed for the measurement of resting myocardial flow (1.04+/-0.37 ml/g/min, n = 11). The noise in our human measurements (SE(flow) = 0.2 ml/g/min) appears to come primarily from residual respiratory motion. Although the current signal-to-noise ratio limits our ability to measure small fluctuations in resting flow accurately, the results indicate that this noninvasive method has great promise for the quantitative assessment of myocardial flow reserve in humans.