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Biomedical subjects

R A Walsh

Publications and source records attributed to R A Walsh.

At least 91 records · Page 5Linked to original sources
PubMed1996

Cardiac-specific overexpression of phospholamban alters calcium kinetics and resultant cardiomyocyte mechanics in transgenic mice.

Phospholamban is the regulator of the cardiac sarcoplasmic reticulum (SR) Ca(2+)-ATPase activity and an important modulator of basal contractility in the heart. To determine whether all the SR Ca(2+)-ATPase enzymes are subject to regulation by phospholamban in vivo, transgenic mice were generated which overexpressed phospholamban in the heart, driven by the cardiac-specific alpha-myosin heavy chain promoter. Quantitative immunoblotting revealed a twofold increase in the phospholamban protein levels in transgenic hearts compared to wild type littermate hearts. The transgenic mice showed no phenotypic alterations and no changes in heart/body weight, heart/lung weight, and cardiomyocyte size. Isolated unloaded cardiac myocytes from transgenic mice exhibited diminished shortening fraction (63%) and decreased rates of shortening (64%) and relengthening (55%) compared to wild type (100%) cardiomyocytes. The decreases in contractile parameters of transgenic cardiomyocytes reflected decreases in the amplitude (83%) of the Ca2+ signal and prolongation (131%) in the time for decay of the Ca2+ signal, which was associated with a decrease in the apparent affinity of the SR Ca(2+)-ATPase for Ca2+ (56%), compared to wild type (100%) cardiomyocytes. In vivo analysis of left ventricular systolic function using M mode and pulsed-wave Doppler echocardiography revealed decreases in fractional shortening (79%) and the normalized mean velocity of circumferential shortening (67%) in transgenic mice compared to wild type (100%) mice. The differences in contractile parameters and Ca2+ kinetics in transgenic cardiomyocytes and the depressed left ventricular systolic function in transgenic mice were abolished upon isoproterenol stimulation. These findings indicate that a fraction of the Ca(2+)-ATPases in native SR is not under regulation by phospholamban. Expression of additional phospholamban molecules results in: (a) inhibition of SR Ca2+ transport; (b) decreases in systolic Ca2+ levels and contractile parameters in ventricular myocytes; and (c) depression of basal left ventricular systolic function in vivo.

Adrenergic beta-Agonists↗
PubMed1996

The role of the cytoskeleton in left ventricular pressure overload hypertrophy and failure.

To characterize alterations in gene expression which may occur during the development of compensated left ventricular pressure overload hypertrophy (CH) and the transition to decompensated congestive heart failure (DH), differential RNA display was used to compare mRNA transcripts from sham operated, 4-week, and 8-week thoracic aorta banded guinea-pigs. Of several regulated transcripts chosen for analysis, one was identified by nucleotide sequence homology as titin, a sarcomeric cytoskeletal protein. By differential display and comparative PCR, titin transcripts were increased in CH and then declined in DH. Comparative PCR of desmin and tubulin demonstrated increased mRNA levels for these cytoskeletal proteins in CH and DH. Western analysis showed associated increases in titin (DH) and desmin (CH and DH) protein expression but no increase in tubulin protein. Isolated Langendorff cardiac mechanics failed to reveal functional differences in either hypertrophy phenotype when microtubules were depolymerized (colchicine 10(-6)M). In summary, the major cytoskeletal proteins are differentially regulated in LV pressure overload hypertrophy and failure. Neither the level of beta-tubulin or its polymerization state appear to affect LV function in this model of cardiac hypertrophy.

Animals↗
PubMed1996

Effects of changes in atrioventricular gradient and contractility on left ventricular filling in human diastolic cardiac dysfunction.

The factors responsible for abnormalities in diastolic filling indexes as assessed by noninvasive testing in human beings have been extensively studied but are not completely understood. We therefore investigated left ventricular diastolic filling indexes by radionuclide angiography during right atrial pacing simultaneously with assessment of a directly measured left atrioventricular gradient and a time constant of isovolumic relaxation in 11 patients with hypertension and diastolic dysfunction. Loading conditions were altered with nitroprusside and phenylephrine, and contractility was improved by dobutamine infusion. The maximum left atrioventricular gradient at constant heart rates was determined by loading conditions and was not significantly affected by increases in contractility or an improvement in isovolumic relaxation rate. The peak filling rate according to radionuclide angiography was highly dependent on the atrioventricular gradient and was not affected by enhancement of the isovolumic relaxation rate.

Adult↗
PubMed1996

The cellular pathophysiology of progression to heart failure.

Congestive heart failure is the final common pathway of diverse etiologies that result in impaired systolic and diastolic function, deleterious activation of neurohumoral pathways, and high morbidity and mortality. Many studies published in 1995 significantly added to our understanding of the pathophysiologies of heart failure at the cellular level. Because a common accompaniment to all forms of low output heart failure are hypertrophy and contractile dysfunction of the cardiomyocyte, applications of the techniques of molecular and cell biology to animal models that demonstrate this phenomenon are providing new insights into the mechanisms responsible for this important clinical problem. In the past year, critical information was derived from animal models that mimic human cardiac hypertrophy and failure. Likewise, genetically engineered mice in which a gene product of interest is overexpressed or eliminated provided critical information, in particular regarding the roles of phospholamban and beta-adrenergic receptor kinase 1 in mediating the contractile responses of the heart to beta-adrenergic stimulation. Furthermore, study of human myocardial tissue from patients with end-stage cardiomyopathy continues to provide insight into the diverse etiologies of heart failure. The recent applications of the techniques of molecular and cell biology to this clinical problem are likely to accelerate our understanding of the complex mechanisms responsible for this syndrome.

Action Potentials↗
PubMed1996

Annexin VI overexpression targeted to heart alters cardiomyocyte function in transgenic mice.

Annexin VI is a member of a family of Ca(2+)-dependent phospholipid-binding proteins that is expressed in many tissues, including the heart. It is a regulator of membrane-associated events, including the skeletal muscle ryanodine-sensitive Ca2+ release channel and the cardiac Na+/Ca2+ exchanger. The potential roles of annexin VI in Ca2+ signaling in cardiac myocytes were evaluated by targeting its overexpression to the hearts of transgenic mice. Expression of full-length human annexin VI cDNA was targeted to the heart using the alpha-myosin heavy chain gene promoter (Subramaniam, A., W. K. Jones, J. Gulick, S. Wert, J. Neumann, and J. Robbins. J. Biol. Chem. 266: 24613-24620, 1991). Five transgenic lines exhibited at least 10-fold overexpression of annexin VI protein in both atria and ventricles. Pathological evaluation indicated mice overexpressing annexin VI had enlarged dilated hearts, acute diffuse myocarditis, lymphocytic infiltration, moderate to severe fibrosis throughout the heart, and mild fibrosis around the pulmonary veins of the lungs. Contractile mechanics of cardiomyocytes isolated from hearts of transgenic animals showed frequency-dependent reduced percent shortening and decreased rates of contraction and relaxation compared with control animals. Cardiomyocytes isolated from transgenic animals had lower basal levels of intracellular free Ca2+ and a reduced rise in free Ca2+ following depolarization. After stimulation, intracellular free Ca2+ returned to basal levels faster in transgenic cells than in cells from control animals. These data demonstrate that the overexpression of annexin VI in the heart disrupts normal Ca2+ homeostasis and suggests that this dysfunction may be due to annexin VI regulation of pumps and/or exchangers in the membranes of cardiomyocytes.

Animals↗
PubMed1996

Effects of thyroid hormone on left ventricular performance and regulation of contractile and Ca(2+)-cycling proteins in the baboon. Implications for the force-frequency and relaxation-frequency relationships.

The transcriptional, posttranscriptional, and related functional effects of thyroid hormone on primate myocardium are poorly understood. Therefore, we studied the effects of thyroid hormone on sarcoplasmic reticulum (SR) Ca(2+)-cycling proteins and myosin heavy chain (MHC) composition at the steady state mRNA and protein level and associated alterations of left ventricular (LV) performance in 8 chronically instrumented baboons. The force-frequency and relaxation-frequency relations were assessed as the response of LV isovolumic contraction (dP/dtmax) and relaxation (Tau), respectively, to incremental atrial pacing. Both the heart rate at which dP/dtmax was maximal and Tau was minimal (critical heart rates) in response to pacing were increased significantly after thyroid hormone. Postmortem LV tissue from 5 thyroid-treated and 4 additional control baboons was assayed for steady state mRNA levels with cDNA probes to MHC isoforms and SR Ca(2+)-cycling proteins. Steady state SR Ca(2+)-ATPase and phospholamban mRNA increased in the hyperthyroid state, and alpha-MHC mRNA appeared de novo, whereas beta-MHC mRNA decreased. Western analysis (4 thyroid-treated and 4 control baboons) showed directionally similar changes in MHC isoforms and a slight increase in SR Ca(2+)-ATPase. In contrast, there was a statistically nonsignificant decrease in phospholamban protein, which resulted in a significant 40% decrease in the ratio of phospholamban to SR Ca(2+)-ATPase. Thus, thyroid hormone increases the transcription of Ca(2+)-cycling proteins and shifts MHC isoform expression in the primate LV. Our data suggest that both transcriptional and posttranslational mechanisms determine the levels of these proteins in the hyperthyroid primate heart and mediate, in part, the observed enhanced basal and frequency-dependent LV performance.

Animals↗
PubMed1995

Disparate effects of early pressure overload hypertrophy on velocity-dependent and force-dependent indices of ventricular performance in the conscious baboon.

BACKGROUND: The effects of early pressure overload on left ventricular (LV) chamber mechanics in the primate heart are poorly understood. METHODS AND RESULTS: To test the hypothesis that early LV pressure overload hypertrophy is associated with depression of velocity-dependent indices of LV systolic (LV dP/dt) and diastolic function (time constant of relaxation, tau) but unchanged systolic elastance (Ees), we studied six conscious baboons instrumented with LV micromanometers and LV dimension and wall thickness sonomicrometers. Loading conditions were altered by pharmacological angiotensin II generation both before and 12 weeks after producing renovascular hypertension (2 kidney, 1 clip). The LV systolic pressure (149 +/- 11 [SD] versus 114 +/- 5 mm Hg) and LV mass (125 +/- 25 versus 91 +/- 20 g) were greater 12 weeks after than before (both P < .05). Both Ees and Ees normalized for LV mass were similar before versus 12 weeks after (23.0 +/- 9.6 versus 22.3 +/- 9.8 mm Hg/mL and 26.5 +/- 14.5 versus 19.8 +/- 12.5 mm Hg/mL, respectively; both P = NS). At matched LV systolic and diastolic pressures, LV fractional shortening was similar (18.6 +/- 6.8% versus 21.6 +/- 4.9%), but the time constant of LV isovolumic relaxation was significantly longer (42.3 +/- 5.3 versus 31.4 +/- 7.0 ms, P < .05) and LV dP/dt and Vcf were significantly less (1891 +/- 352 versus 2342 +/- 284 mm Hg/s and 0.9 +/- 0.4 versus 1.1 +/- 0.3 circ/s, respectively; both P < .05) 12 weeks after than before. CONCLUSIONS: In conscious baboons with systemic arterial hypertension and early LV hypertrophy, there is depression of velocity-dependent indices of LV contraction and relaxation but unaltered force-dependent measures of contractility.

Animals↗
PubMed1995

Mechanisms, diagnosis, and treatment of diastolic heart failure.

Diastolic heart failure, in the absence of LV systolic dysfunction, is a common clinical condition that can be demonstrated in as many as one third of patients with congestive heart failure. Diastolic dysfunction caused by abnormalities in LV filling can be a result of many pathologic conditions, including hypertrophy, infiltrative cardiomyopathies, or myocardial ischemia. The major physiologic determinants of LV filling can be divided into cellular mechanisms, hemodynamic characteristics, and hormonal influences. Cellular mechanisms for impaired LV inactivation are determined by the handling of calcium within the myocyte during excitation-contraction-relaxation coupling. The hemodynamic characteristics of LV diastolic filling are determined by loading conditions, the time constant of isovolumic relaxation, heart rate, ventricular nonuniformity, pericardial restraint, myocardial elasticity, chamber compliance, and coronary blood flow. The sympathetic nervous system and the renin-angiotensin system are important modulators of diastolic filling, directly or indirectly. The diagnosis of heart failure is confirmed by a combination of clinical tests including invasive and noninvasive techniques, each of which has advantages and disadvantages. Treatment of medical conditions in which diastolic heart failure is a prominent component include pharmacotherapy with calcium channel antagonists, beta-adrenergic blocking agents, diuretic agents, and angiotensin-converting-enzyme inhibitors. Certain conditions associated with diastolic filling abnormalities such as pericardial disease or severe ischemic heart disease may be best managed by surgical or percutaneous intervention. Future research will include further delineation of the cellular mechanisms of active myocardial relaxation and clinical investigation into treatment directed at improving outcome.

Diagnosis, Differential↗
PubMed1995

A rapid diagnostic and treatment center for patients with chest pain in the emergency department.

STUDY OBJECTIVE: To evaluate a comprehensive diagnostic 9-hour evaluation (Heart ER Program) for patients with possible acute ischemic coronary syndromes. DESIGN: Retrospective review of consecutive patients. SETTING: Urban tertiary care emergency department. PARTICIPANTS: A total of 1,010 patients with symptoms suggestive of acute ischemic coronary syndrome was enrolled in the Heart ER Program over the first 32 months of operation. Patients with history of coronary artery disease, hemodynamic instability, acute ST-segment elevation or depression of more than 1 mm, or a clinical syndrome consistent with unstable angina were directly admitted to the hospital. INTERVENTION: Patients underwent serial testing for creatine kinase (CK-MB) on presentation to the Heart ER and 3, 6, and 9 hours later with continuous 12-lead ECGs/serial ST-segment trend monitoring for 9 hours. Two-dimensional echocardiography and graded exercise testing were performed in the ED after the 9-hour evaluation period. RESULTS: Of 1,010 patients, 829 (82.1%) were released home from the ED; 153 (15.1%) required admission for further cardiac evaluation. Fifty-two of 153 (33.9%) admitted patients were found to have a cardiac cause for their symptoms; 43 had acute ischemic coronary syndromes (12, acute myocardial infarction; 31, angina or unstable angina). CONCLUSION: The Heart ER program provides an effective method for evaluating low- to moderate-risk patients with possible acute ischemic coronary syndrome in the ED setting.

Adult↗
PubMed1995

Smoking cessation in pregnancy: a survey of the medical and nursing directors of public antenatal clinics in Australia.

Smoking is a major cause of adverse pregnancy outcomes. However limited data are available documenting the perceptions of care providers in this area. This mail survey undertaken in 1992-1993 aimed to assess the smoking cessation practices of Australian public antenatal clinics. Questionnaires were returned by 140 (80%) of the 175 eligible hospitals, 83 (48%) medical directors and 108 (62%) nursing directors. Smoking advice was rated an essential activity at the first antenatal visit by 69% of responding directors. Nonetheless, only 12% of clinics indicated they offered relevant training and 4% reported written policies. Results also indicate senior staff may have suboptimal levels of awareness of smoking risks. Clinics used a narrow array of strategies to promote cessation. Almost one-third of directors said they advised smokers to cut down rather than stop smoking completely. There is a need for antenatal clinics to implement integrated strategies for the detection and treatment of pregnant smokers including staff training and modifications to the clinics' environment. In addition, major health promotion agencies need to develop effective smoking cessation programmes designed specifically for use in antenatal clinics and to monitor their on-going implementation.

Australia↗
PubMed1995

Smoking by adolescents: large revenue but little for prevention.

The purpose of this paper is to report on the government revenue gained from the sale of cigarettes to minors and the proportion of this revenue that is spent on attempting to prevent adolescents from taking up this habit. Prevalence of smoking by minors was extrapolated for the individual states using Australian prevalence data; estimates of annual cigarette consumption were coupled with the respective cost of cigarettes in each state to derive an estimate of the total revenue accumulating from cigarette consumption by minors. From our analysis, approximately 211,000 Australian children under the legal age to purchase cigarettes consumed approximately 11.5 million packets of cigarettes in 1990. The estimated tax revenues to the federal and state governments from these sales were $8.42 million and $12.78 million respectively. While the average state revenue from cigarette consumption by minors during 1990 was just over $60 per under-age smoker, only $0.11 per under-age smoker was spent on anti-smoking campaigns in 1990. This is equivalent to approximately 0.002 per cent of state revenue from cigarette smoking by those under the legal purchase age being spent on discouraging adolescents from taking up this habit. Clearly, there is an inequitable expenditure on antismoking activities, given the enormous resources obtained from sales to minors.

Adolescent↗
PubMed1995

In vivo echocardiographic detection of enhanced left ventricular function in gene-targeted mice with phospholamban deficiency.

We evaluated the ability of M-mode and Doppler echocardiography to assess left ventricular (LV) function reliably and repeatedly in mice and tested whether these techniques could detect physiological alterations in phospholamban (PLB)-deficient mice. Anesthetized wild-type mice (n = 7) and mice deficient in PLB (n = 8) were studied with two-dimensional guided M-mode and Doppler echocardiography using a 9-MHz imaging and 5- to 7.5-MHz Doppler transducer. Data were acquired in the baseline state and after intraperitoneal isoproterenol administration (2.0 micrograms/g IP). Interobserver and intraobserver variability and reproducibility were excellent. PLB-deficient mice were associated with significant (P < .05) increases in several physiological parameters (mean +/- SD) compared with wild-type control mice: normalized mean velocity of circumferential shortening (7.7 +/- 2.1 versus 5.5 +/- 1.0 circ/sec), peak aortic velocity (105 +/- 13 versus 75 +/- 9.2 cm/s), mean aortic acceleration (57 +/- 16 versus 31 +/- 4 m/s2), and peak early-diastolic transmitral velocity (80.0 +/- 7.2 versus 66.9 +/- 7.7 cm/s). LV dimensions, shortening fractions, heart rates, late diastolic transmitral (A) velocities, and early to late (E/A) diastolic velocity ratios were similar in both groups. Isoproterenol administration resulted in significant increases in Doppler indices of ventricular function in control but not PLB-deficient mice. These findings indicate that assessment of LV function can be performed noninvasively in mice under varying physiological conditions and that PLB regulates basal LV function in vivo.

Animals↗
PubMed1995

Differential changes in cardiac phospholamban and sarcoplasmic reticular Ca(2+)-ATPase protein levels. Effects on Ca2+ transport and mechanics in compensated pressure-overload hypertrophy and congestive heart failure.

The objective of this study was to elucidate the role of the sarcoplasmic reticulum (SR) in the transition from compensated pressure-overload hypertrophy (increased left ventricular [LV] mass, normal LV function, and no pulmonary congestion) to congestive heart failure (increased LV mass, depressed LV function, and pulmonary congestion). To address this issue, the descending thoracic aorta was banded for 4 and 8 weeks in adult guinea pigs, and the changes in isovolumic LV mechanics, SR Ca2+ transport, and SR protein levels were determined and compared with age-matched sham-operated control animals. A subgroup of the 8-week banded animals manifested the congestive heart failure phenotype with diminished developed LV pressure normalized by LV mass, reduced rates of LV pressure development and relaxation, and markedly increased lung weight-to-body weight ratios. The cardiac mechanical and morphometric changes were associated with depressed protein levels of the SR Ca(2+)-ATPase (85% of the control) and phospholamban (65% of the control) assessed by quantitative immunoblotting. Resultant rates of SR Ca2+ uptake (Vmax) and the affinity of SR Ca(2+)-ATPase for Ca2+ (EC50) were significantly depressed [32 +/- 6 nmol Ca2+.min-1.mg-1 and 0.59 +/- 0.12 (mumol/L)/L, respectively] compared with the 8-week sham-operated control animals [40 +/- 1 nmol Ca2+.min-1.mg-1 and 0.40 +/- 0.05 (mumol/L)/L, respectively]. We conclude that this model of pressure overload-induced cardiac failure is associated with (1) diminished LV force development, rates of pressure development, and decay; (2) depressed protein expression of the Ca(2+)-cycling proteins SR Ca(2+)-ATPase and phospholamban; and (3) decreased Vmax and affinity of the SR Ca(2+)-ATPase for Ca2+.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Effects of angiotensin II generated by an angiotensin converting enzyme-independent pathway on left ventricular performance in the conscious baboon.

Human chymase is a serine proteinase that converts angiotensin (Ang) I to Ang II independent of angiotensin converting enzyme (ACE) in vitro. The effects of chymase on systemic hemodynamics and left ventricular function in vivo were studied in nine conscious baboons instrumented with a LV micromanometer and LV minor axis and wall thickness sonomicrometer crystal pairs. Measurements were made at baseline and after [Pro11DAla12] Ang I, a specific substrate for human chymase, was given in consecutive fashion as a 0.1 mg bolus, an hour-long intravenous infusion of 5 mg, a 3 mg bolus, and after 5 mg of an Ang II receptor antagonist. [Pro11DAla12]Ang I significantly increased LV systolic and diastolic pressure, LV end-diastolic and end systolic dimensions and the time constant of LV relaxation and significantly decreased LV fractional shortening and wall thickening. Administration of a specific Ang II receptor antagonist reversed all the hemodynamic changes. In separate studies, similar results were obtained in six of the baboons with ACE blockade (20 mg, intravenous captopril). Post-mortem studies indicated that chymase-like activity was widely distributed in multiple tissues. Thus, in primates, Ang I is converted into Ang II by an enzyme with chymase-like activity. This study provides the first in vivo evidence of an ACE-independent pathway for Ang II production.

Angiotensin I↗
PubMed1995

Left atrial mechanical and biochemical adaptation to pacing induced heart failure.

OBJECTIVE: To determine the left atrial mechanical and biochemical adaptations to congestive heart failure, 10 dogs with rapid atrial and ventricular pacing and seven control dogs were studied. METHODS: Animals were instrumented with left atrial sonomicrometers and micromanometers and left atrial pressure-volume relationships were generated by phenylephrine boluses for maximum elastance (Emax) and end systolic elastance (Ees) calculations. Left atrial maximum volume, ejection fraction, and mean circumferential fibre shortening (Vcf) were compared at matched left atrial pressure. At necropsy, myosin heavy chain (MHC) isoforms from the left atrial body and appendage were separated with SDS-PAGE, stained with monoclonal antibodies to alpha and beta MHC, and quantified with laser densitometry. RESULTS: Left atrial ejection fraction and Vcf were significantly lower and maximum atrial volume and atrial systolic stroke volume were significantly greater in heart failure than in control. Emax was not significantly altered in heart failure, at 5.9(SD 2.9) v 4.5(1.6) mm Hg.ml-1 in controls. However, Vcf was lower (P < 0.05) and the A loop pressure-volume area (an index of eternal mechanical work performed by the left atrium) was greater (P < 0.05) in heart failure than in control dogs. The percent beta MHC in the left atrial body was greater in dogs with heart failure than in controls, at 42.6(9.8) v 17.3(9.0)%, P < 0.05. By contrast there was no significant beta MHC isoform switch in the left atrial appendage [14.4(7.6) v 17.9(9.7)%]. CONCLUSIONS: In this model of left atrial pressure and volume overload, there is significant upregulation of beta MHC in the left atrial body but not in the appendage and this isoform switch is associated with decreased velocity of left atrial contraction, increased atrial mechanical work, and unchanged force generation.

Animals↗
PubMed1995

Medical education about alcohol: review of its role and effectiveness.

Many reports have described inadequate responses by doctors to problems associated with alcohol misuse. Low levels of medical knowledge and inappropriate attitudes continue to be documented in the alcohol area. However, in recent years, greater emphasis has been placed on the need to improve doctors' skills in relation to alcohol problem detection and intervention. Experiential teaching approaches have been recommended and strategies which incorporate feedback methods offer considerable promise. In the United Kingdom and Canada, there has been no centrally funded approach to improve alcohol medical education. In contrast, federally funded initiatives in the United States of America and Australia have been associated with impressive increases in alcohol-related teaching hours and elective opportunities. Despite the substantial effort invested in achieving these curriculum gains, there is a dearth of research demonstrating impacts on medical behaviours or evaluating the cost-effectiveness of different educational strategies. Evidence from trials in smoking cessation training indicate that well-designed programmes can alter doctor behaviours in relation to substance abuse. If the alcohol medical education field is to progress, there is an urgent need for the development and evaluation of programmes which are better designed and are more informed by theory.

Alcoholism↗
PubMed1994

Effects of a novel inotropic agent (OPC-18790) on systolic and diastolic function in patients with severe heart failure.

A double-blind placebo-controlled study to determine the acute hemodynamic and cardiac mechanical effects of the quinolinone derivative OPC-18790 was performed in 12 patients with New York Heart Association class III or IV congestive heart failure. Simultaneous echocardiographic, Doppler, and invasive hemodynamic studies were performed before and after a 6-hour intravenous infusion of drug at 2.5, 5.0, or 10.0 micrograms/kg/min or of placebo. OPC-18790 (mean dose 5.9 +/- 3.5 mg) caused significant increases in left ventricular (LV) ejection fraction (15% +/- 4% vs 23% +/- 5%; p < 0.05) and cardiac index (1.7 +/- 0.4 vs 2.5 +/- 0.6 L/min/m2; p < 0.05) and a rightward and upward shift in the stress-shortening relation. LV end-diastolic volume and heart rate were unchanged. LV filling and posterior LV wall thinning rates from digitized M-mode echocardiographic studies (0.49 +/- 0.16 vs 0.75 +/- 0.21 cm/sec and 2.0 +/- 0.9 vs 3.0 +/- 1.4 cm/sec, respectively; both p < 0.05), transmitral deceleration time (67 +/- 24 vs 81 +/- 19 msec, p < 0.05), and atrial filling fraction (31.0% +/- 11.2% vs 38.9% +/- 13.9%, p < 0.05) increased with OPC-18790 infusion. Despite a significant decrease in pulmonary capillary wedge pressure (28 +/- 9 vs 18 +/- 10 mm Hg) there was no change in the velocity-time integral of early diastolic filling (53 +/- 12 vs 59 +/- 22 cm), suggesting improved LV relaxation. Hemodynamics and parameters of LV function were unchanged in the 3 patients receiving placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗