Comparison of the effects of ORG 30029, dobutamine and high perfusate calcium on function and metabolism in rat heart.

Cardiac contractility may be enhanced via multiple cellular mechanisms resulting in varied effects on cardiac energetics. The mechanisms that account for the varied energetic responses are not well understood. The purpose of this investigation was to compare the effects of the calcium sensitizing agent ORG 30029 (N-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximidamide hydrochloride, a calcium sensitizing agent which increases contractility without increasing calcium transients significantly), dobutamine and high perfusate calcium on contractility and energetics. Langendorff-perfused rat hearts were stimulated with ORG 30029, dobutamine and high perfusate calcium in graduated concentrations while myocardial oxygen consumption (MVO2) and force-time integral were measured. ORG 30029, dobutamine and high perfusate calcium increased contractility in a dose-dependent manner. Despite an increase of 50% in systolic pressure and a 17% increase in force-time integral from control, ORG 30029 had no significant effect on MVO2 at the lower concentrations (n = 6). However, dobutamine (n = 4) and high perfusate calcium (n = 4) caused a 65% increase in systolic pressure and a 17% increase in force-time integral and a 50% and 41% increase in MVO2 respectively (P < 0.05). High energy phosphates (by 31P NMR), and lactate production were unaltered by these agents, suggesting that metabolism was steady state. Basal metabolism tended to increase slightly with dobutamine but not with ORG 30029 or high perfusate calcium. ORG 30029, dobutamine, and high perfusate calcium increase contractility in perfused rat hearts with disparate effects on energetics. These differences may be accounted for, in part, by differences in energy expenditure for calcium handling.

Functional and energetic effects of the inotropic agents EMD-57033 and BAPTA on the isolated rat heart.

This investigation studied the functional and energetic effects of the novel positive inotropic agent EMD-57033 and the negative inotropic agent 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) in the paced Langendorff-perfused rat heart. EMD-57033 is a calcium-sensitizing agent that has previously been shown to increase contractility without affecting calcium transients. Its effects were compared with that of dobutamine, which increases contractility by increasing calcium transient amplitude. EMD-57033 (2 microM) and dobutamine (0.2 microM) induced a 40% increase in developed pressure. Myocardial oxygen consumption (MVO2) increased significantly with dobutamine. However, there was no significant change in MVO2 with EMD-57033. There was no change in phosphate metabolite concentrations as detected by 31P-nuclear magnetic resonance with either agent. Lactate production and basal metabolism were unaffected by either agent. Thus EMD-57033 increased contractility in a more energetically economical manner than did dobutamine. Contractility was decreased with BAPTA, an intracellular calcium chelator that decreases contractility by binding free calcium. The metabolic effects of BAPTA (2.2 microM) were compared with those of verapamil (10 nM), an agent which decreases calcium fluxes. Both agents decreased developed pressure 60%. MVO2 decreased 14% with BAPTA and 50% with verapamil. Neither agent altered the concentrations of phosphate metabolites, lactate production, or basal metabolism. Thus BAPTA lowered contractility in a less energetically economical manner than verapamil. These data suggest that in rat hearts, inotropic agents with different effects on calcium handling have different effects on energetics.

Abnormal left ventricular ejection fraction response to mental stress and exercise in cardiomyopathy.

BACKGROUND: A decline in left ventricular (LV) ejection fraction in response to mental stress and exercise is regarded as an indicator of myocardial ischemia. In patients with LV dysfunction, the ejection fraction is sensitive to afterload, which increases during stress. Thus, the effects of mental stress and exercise on LV systolic function in patients with cardiomyopathy were examined. METHODS: The ambulatory nuclear VEST (Capintec, Inc., Ramsey, N.J.) was used to monitor LV ejection fraction in patients with cardiomyopathy (10 idiopathic and 9 ischemic). Patients underwent a series of mental stress tests (serial 7s, Stroop color, and Paced auditory addition) and treadmill exercise. Heart rate, systolic blood pressure, and LV ejection fraction were measured. RESULTS: Mental stress and exercise increased heart rate and systolic blood pressure. For idiopathic cardiomyopathy, LV ejection fraction decreased during serial 7s, Stroop color, Paced auditory addition and exercise by -8% +/- 6%, -7% +/- 5%, -7% +/- 3%, -9% +/- 10%, respectively. For ischemic cardiomyopathy, LV ejection fraction declined by -4% +/- 3%, -7% +/- 5%, -6% +/- 3%, -2% +/- 6% during the same stress tests. There was no difference between the idiopathic and ischemic groups. Each patient showed a 5% or greater decline in LV ejection fraction during one mental stress test. There was an inverse relation between changes in LV ejection fraction and systolic blood pressure during all mental stress tests and exercise (r = -0.47, p < 0.0001). CONCLUSIONS: In patients with depressed baseline systolic function, the decline in systolic function during mental stress and exercise could be related in part to increases in LV afterload.

Relationship between hemodynamics and right ventricular function in patients with cardiomyopathy. Important role of tricuspid regurgitation.

STUDY OBJECTIVE: Right ventricular (RV) ejection fraction is load sensitive, varying inversely with pulmonary artery pressure. We tested whether this relationship exists in dilated cardiomyopathy. DESIGN: Retrospective chart review. SETTING: Tertiary care referral medical center. PATIENTS: In 25 patients with cardiomyopathy referred for heart transplant evaluation (left ventricular ejection fraction 27 +/- 12%), hemodynamics, radionuclide angiograms, and Doppler echocardiograms were obtained initially (study A) and 8 +/- 8 months later (study B). RESULTS: Right ventricular ejection fraction was 40 +/- 17% on study A and 41 +/- 16% on study B, with a wide range of change between studies (+38 to -28%). Pulmonary artery systolic pressure (PASP) and right atrial pressure increased (52 +/- 9 to 61 +/- 10 mm Hg and 10 +/- 4 to 14 +/- 4 mm Hg, respectively, p < 0.05). There was no relation between PASP and RV ejection fraction (n = 50, r = -0.02, p = 0.87). Also, there was no relation between changes in PASP and RV ejection fraction (n = 25, r = 0.25, p = 0.15) between study A and B. However, there was a significant relation between interstudy changes in PASP and RV ejection fraction (n = 14, r = -0.71, p = 0.005) and end-systolic volume (n = 14, r = 0.53, p < 0.05) in patients in whom the degree of tricuspid regurgitation was either none or mild on both study A and B. CONCLUSIONS: In patients with cardiomyopathy, RV ejection fraction cannot be used as a noninvasive marker of pulmonary hypertension. Owing to variation in tricuspid regurgitation, alterations in pulmonary artery pressure over time may not lead to the expected change in RV ejection fraction or end-systolic volume.

Tissue specific perfusion imaging using arterial spin labeling.

Quantitative magnetic resonance measurements of regional tissue perfusion can be obtained using magnetically labeled arterial water as a diffusable tracer. Continuous labeling is achieved in flowing spins using adiabatic inversion. The effects of continuous labeling of proximal arterial spins and T1 relaxation in distal tissue magnetization result in a steady-state change in tissue magnetization which is tissue specific, i.e., it can be quantified in units of blood flow per gram of tissue per unit time. This magnetization is sampled using standard imaging sequences. The theoretical basis for this method, including the effects of macromolecular spin saturation, is reviewed. Recent results demonstrating the successful implementation of this technique in vitro and in vivo in rat brain, heart, and kidney, and in human brain and kidney are presented, as well as the use of a separate RF coil for arterial labeling to produce selective perfusion images in rat brain. This approach allows quantitative perfusion images to be obtained completely non-invasively at the resolution of 1H MRI, and is useful in the clinical and investigational evaluation of organ physiology.

Effects of chronic right ventricular pressure overload on left ventricular diastolic function.

Right ventricular (RV) function influences left ventricular (LV) diastolic filling in various clinical and experimental models. The influence of RV systolic function on LV diastolic performance was examined in patients with severe RV pressure overload. Eighty-two patients with pulmonary vascular or parenchymal disease who were referred for heart-lung or lung transplant evaluation were studied. All patients had radionuclide angiography from which RV ejection fraction and LV peak filling rate were measured. Most patients (n = 51) had right-sided cardiac catheterization. In 24 patients (group 1), RV ejection fraction was < 30%, whereas in 58 (group 2), it was > 30%. Mean pulmonary artery pressure was greater in group 1 than in 2 (57 +/- 16 vs 34 +/- 20 mm Hg; p < 0.0001). Pulmonary artery wedge pressure was also greater in group 1 than in 2 (14 +/- 9 vs 7 +/- 2 mm Hg; p < 0.0001), whereas peak filling rate was decreased (2.16 +/- 0.88 vs 2.97 +/- 0.79 end-diastolic volumes/s; p < 0.0001). LV ejection fraction was normal in all patients. There was an inverse relation between RV ejection fraction and pulmonary artery wedge pressure (r = 0.45; p < 0.001; SEE 5.3). There was a direct relation between RV ejection fraction and LV peak filling rate (r = 0.49; p < 0.0001; SEE 1.34). In patients with RV pressure overload, RV systolic function is related to LV diastolic performance. This effect is most likely mediated by ventricular interdependence.

Right ventricular thallium-201 kinetics in pulmonary hypertension: relation to right ventricular size and function.

Right ventricular ischemia occurs in experimental models of pulmonary hypertension. We analyzed right ventricular size and function and 201Tl uptake to determine if there was a relationship between 201Tl uptake and systolic function in 19 patients with pulmonary artery hypertension who were being evaluated for heart-lung transplantation. All patients had dipyridamole stress 201Tl scintigraphy, radionuclide angiography and echocardiography. In nine patients (Group 1), right ventricular ejection fraction was < 30% (mean 22% +/- 8%). In 10 patients (Group 2) it was > 30% (mean 45% +/- 11%). In Group 1, right ventricular 201Tl uptake in the lateral wall after dipyridamole was increased compared to Group 2 (40% +/- 7% versus 28% +/- 15% counts/pixel, p < 0.05) while left ventricular free wall uptake was similar. The ratio of right to left ventricular 201Tl uptake was increased in Group 1 versus Group 2 (0.81% +/- 0.30% versus 0.49% +/- 0.18%, p < 0.05). At 4 hr, right ventricular free wall 201Tl clearance was comparable, 51% +/- 13% versus 51% +/- 18% in Groups 1 and 2, respectively. No patient had perfusion abnormalities. Right ventricular ejection fraction was inversely related to dipyridamole stress right ventricular 201Tl uptake, r = -0.49, p < 0.03, s.e.e. = 13.6. Right ventricular 201Tl uptake was directly related to right ventricular wall thickness (r = 0.56, p = 0.18, s.e.e. = 10.4). Therefore, patients with more severe right ventricular systolic dysfunction have greater 201Tl uptake after dipyridamole stress, suggesting increased myocardial mass and possibly blood flow in response to hypertrophy. Patients with the most marked hypertrophy have impairment of right ventricular systolic function, independent of ischemia.

Magnetic resonance imaging of perfusion in the isolated rat heart using spin inversion of arterial water.

Measurement of regional myocardial perfusion is important for the diagnosis and treatment of coronary artery disease. Currently used methods for the measurement of myocardial tissue perfusion are either invasive or not quantitative. Here, we demonstrate a technique for the measurement of myocardial perfusion using magnetic resonance imaging (MRI) with spin tagging of arterial water. In addition, it is shown that changes in perfusion can be quantitated by measuring changes in tissue T1. Perfusion images are obtained in Langendorff-perfused, isolated rat hearts for perfusion rates ranging from 5 to 22 ml/g/min. The MRI-determined perfusion rates are in excellent agreement with perfusion rates determined from measurement of bulk perfusate flow (r = 0.98). The predicted linear dependence of the measured T1 (T1app) on perfusion is also demonstrated. The ability of perfusion imaging to measure regional variations in flow is demonstrated with hearts in which perfusion defects were created by ligation of a coronary artery. These results indicate that MRI of perfusion using spin inversion of arterial water gives quantitative maps of cardiac perfusion.

Relationship of the renin-angiotensin system and systemic arterial pressure to sodium excretion during atrial natriuretic peptide infusion in men.

The goal of this study was to evaluate the relative contribution of the renin-angiotensin system and mean arterial pressure to sodium excretion and urine flow rate during an infusion of atrial natriuretic peptide (ANP) at physiologically relevant doses in humans. Eight normal volunteers were studied during five periods: (1) baseline in the supine position; (2) during an infusion of ANP at physiologic doses (0.01 micrograms/kg/min) in the supine position; (3) during ANP infusion and 60 degrees head-up tilt; (4) during ANP infusion, head-up tilt, and interruption of the renin-angiotensin axis with the angiotensin converting enzyme inhibitor (ACEI) enalaprilat; and (5) in the supine position during ANP infusion and ACEI. Infusion of ANP in the supine posture significantly increased urine flow rate and sodium excretion compared to baseline while mean arterial pressure and plasma renin activity were unchanged. During head-up tilt and ANP infusion, urine flow rate and sodium excretion were no longer significantly elevated over baseline while mean arterial pressure decreased and plasma angiotensin II levels increased. Addition of ACEI caused a marked diminution of urine flow rate and sodium excretion compared to baseline levels despite continued ANP infusion. Although mean arterial pressure after ACEI administration was lower than baseline, it was not significantly different from the non-ACEI head-up tilt state. Placing subjects in the supine position during ANP infusion and ACEI administration increased mean arterial pressure to levels that were no longer different from baseline, but urine flow rate and sodium excretion remained significantly depressed to the same degree as during head-up tilt with ACEI.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential effects of atrial natriuretic peptide infusion at physiological doses in different postures in humans.

To evaluate potential physiological actions of atrial natriuretic peptide (ANP) in humans, normal male volunteers were studied in the supine and head-up tilt positions both in the absence and presence of an ANP infusion at a rate which increased plasma ANP levels to ranges observed during physiological stimuli such as volume expansion. Infusion of ANP in the supine position provoked a significant natriuresis and diuresis and suppressed aldosterone secretion. Head-up tilt alone caused expected decreases in urine flow rate and the absolute and fractional excretion rates of sodium and increases in plasma renin activity and aldosterone levels. The combination of head-up tilt and ANP infusion resulted in a less marked decrease in urine flow rate and sodium excretion and a similar increase in plasma renin activity. However, there was a significant decrease in plasma aldosterone levels. These data support a physiologic action of ANP on renal and adrenal function.