Longitudinal studies of cardiac troponin I concentrations in serum from male cynomolgus monkeys: resting values and effects of oral and intravenous dosing on biologic variability.

BACKGROUND: There is a paucity of information regarding cardiac troponin (cTn) concentrations in peripheral blood of nonhuman primates (NHP). Even less is known regarding cTn concentrations in monkeys that are restrained for oral or intravenous (iv) dosing. OBJECTIVES: The objectives of these studies were to (1) determine cardiac troponin I (cTnI) concentration in resting Cynomolgus monkeys and investigate biologic variability in cTnI concentration over time, (2) determine cTnI changes in restrained monkeys given sham oral dosing, and (3) determine cTnI changes in restrained NHP given a sham intravenous dosing. METHODS: The Research Use Only Erenna cTnI ultrasensitive immunoassay based on single molecule counting technology was used to determine serum cTnI concentration in longitudinal studies of male Cynomolgus monkeys at rest, and after sham oral and intravenous dosing. Animals were catheterized prestudy, and blood samples were collected by an automated sampling device to limit disturbance of the animals during studies. RESULTS: In resting monkeys cTnI concentrations were relatively low and constant and ranged from 0.2 to 9.6 pg/mL (mean = 2.5 pg/mL), with minimal variability during a 24-hour period. Animals given sham oral dosing also had low cTnI concentration with little variability similar to the resting values. Several animals restrained for intravenous dosing had a small transient increase in cTnI concentration (~5-25 pg/mL) that resolved quickly within one to 3 hours postinjection. CONCLUSIONS: Results of this longitudinal study provide information that may be important in differentiating effects of animal handling from those associated with compound-related effects in preclinical toxicology studies of drugs in development.

Hemodynamic changes in hyperthyroidism-related pulmonary hypertension: a prospective echocardiographic study.

CONTEXT: Recent reports suggest an association between hyperthyroidism and pulmonary hypertension (PHT), although the potential mechanisms and clinical implications remain unclear. OBJECTIVE: Our objective was to determine the prevalence of PHT related to hyperthyroidism and the associated hemodynamic changes and outcome. METHODS AND RESULTS: We performed serial echocardiographic examinations in 75 consecutive patients with hyperthyroidism (43 +/- 2 yr, 47 women) to estimate pulmonary artery systolic pressure (PASP), cardiac output (CO), total vascular resistance (TVR), and left ventricular (LV) filling pressure. Examinations were performed at baseline and 6 months after initiation of antithyroid treatment. Results were compared with 35 age- and sex-matched healthy controls. All hyperthyroid patients had normal LV systolic function, and 35 patients (47%) had PHT with PASP of at least 35 mm Hg. There were no significant differences in the clinical characteristics of hyperthyroid patients with or without PHT (all P > 0.05). Nonetheless, those with PHT had significantly higher CO, PASP, peak transmitral early diastolic flow velocity (E), and ratio of E to early diastolic mitral annular velocity (E') compared with those without PHT and controls (all P < 0.05). Hyperthyroid patients with PHT also had significantly lower TVR than controls (P < 0.05). Among the 35 hyperthyroid patients with PHT, 25 (71%) had pulmonary arterial hypertension (PAH) with normal E/E', and 10 (29%) had pulmonary venous hypertension (PVH) with elevated E/E'. Hyperthyroid patients with PAH had a significantly higher CO and a lower TVR compared with those with PVH. In contrast, hyperthyroid patients with PVH had lower E' and a higher E/E' ratio compared with those with PAH. These hemodynamic abnormalities and PHT were reversible in patients with PAH or PVH after restoration to a euthyroid state. CONCLUSION: In patients with hyperthyroidism and normal LV systolic function, up to 47% had PHT due to either PAH with increased CO (70%) or PVH with elevated LV filling pressure (30%). Most importantly, hyperthyroidism-related PHT was largely asymptomatic and reversible after restoration to a euthyroid state.

Cardiac resynchronization therapy optimization by ultrasonic cardiac output monitoring (USCOM) device.

OBJECTIVES: We investigated the accuracy and feasibility of a 2D echo-independent ultrasonic continuous wave Doppler cardiac output monitoring device (USCOM) operated by trained nurse for the atrio-ventricular interval (AVI) optimization in cardiac resynchronization therapy (CRT). BACKGROUND: CRT is of proven benefit in patients with advanced chronic heart failure and ventricular conduction delay. Appropriate AVI selection is critical to optimize hemodynamic in CRT. Currently, most non-invasive methods for AVI optimization are often complicated and labor-intensive. METHODS: USCOM method, Ritter method, and aortic outflow cardiac output method were used to determine the optima AVI in 20 patients with CRT. The accuracy and time for measurement of each method were determined. RESULTS: The optimal AVI determined by USCOM method had good correlation with Ritter's method and aortic outflow estimated cardiac output method (r2= 0.78, P < 0.01 and r2= 0.73, P < 0.01, respectively). The optimal AVI determined USCOM method showed good agreement (within 10 msec range) with Ritter's method (85% patients) and aortic outflow estimated cardiac output method (80%). The mean time for determining AVI using USCOM method was shorter than that with aortic outflow method (7.1 +/- 0.7 min vs 12.7 +/- 1.1 min, P < 0.01), whereas the mean time was shortest for Ritter method (4.7 +/- 1.6 min vs 7.1 +/- 0.7 min, P < 0.01). CONCLUSION: USCOM device operated by trained nurse can provide a simple, accurate, and fast non-invasive method for the AVI optimization in CRT population.

Effects of oral arsenic trioxide therapy on QT intervals in patients with acute promyelocytic leukemia: implications for long-term cardiac safety.

Ventricular tachyarrhythmias may occur during intravenous arsenic trioxide (As2O3). This has not happened during oral As2O3. Sixteen patients were studied by electrocardiography and 24-hour Holter monitoring at baseline, during and after oral As2O3 (As2O3-ON, As2O3-OFF). QT and corrected QT (QTc) were significantly longer during As2O3-ON than in As2O3-OFF, but QT and QTc dispersions were comparable. The patients' 24-hour heart rates were higher during As2O3-ON than in As2O3-OFF. QTc intervals at each hour were longer during As2O3-ON than in As2O3-OFF. However, QTc prolongation of more than 30 milliseconds only occurred at one time point (2 hours) after oral As2O3, resulting in QTc of more than 500 milliseconds in 3 of 16 patients, all within 4 hours of oral As2O3. Although the standard deviation of normal RR interval was lower during As2O3-ON, ratios of low frequency to high frequency power for As2O3-ON and As2O3-OFF were comparable. No ventricular proarrhythmias were observed. These observations, due to the lower peak plasma arsenic reached during oral As2O3, may explain the relative cardiac safety of oral As2O3.