CHAPERONIN 20 mediates iron superoxide dismutase (FeSOD) activity independent of its co-chaperonin role in Arabidopsis chloroplasts.

Iron superoxide dismutases (FeSODs; FSDs) are primary antioxidant enzymes in Arabidopsis thaliana chloroplasts. The stromal FSD1 conferred the only detectable FeSOD activity, whereas the thylakoid membrane- and nucleoid-co-localized FSD2 and FSD3 double mutant showed arrested chloroplast development. FeSOD requires cofactor Fe for its activity, but its mechanism of activation is unclear. We used reversed-phase high-performance liquid chromatography (HPLC), gel filtration chromatography, LC-MS/MS, protoplast transient expression and virus-induced gene silencing (VIGS) analyses to identify and characterize a factor involved in FeSOD activation. We identified the chloroplast-localized co-chaperonin CHAPERONIN 20 (CPN20) as a mediator of FeSOD activation by direct interaction. The relationship between CPN20 and FeSOD was confirmed by in vitro experiments showing that CPN20 alone could enhance FSD1, FSD2 and FSD3 activity. The in vivo results showed that CPN20-overexpressing mutants and mutants with defective co-chaperonin activity increased FSD1 activity, without changing the chaperonin CPN60 protein level, and VIGS-induced downregulation of CPN20 also led to decreased FeSOD activity. Our findings reveal that CPN20 can mediate FeSOD activation in chloroplasts, a role independent of its known function in the chaperonin system.

Reward System in Late-Life Depression: a Cross-Sectional Case-Control Study.

OBJECTIVE: Anhedonia, commonly defined as a reduced ability to feel pleasure, is a core clinical symptom of late-life depression (LLD). Deficits in reward processing are hypothesised to be associated with anhedonia. We examined differences in reward sensitivity between patients with LLD and healthy controls and explored the associations between LLD-related symptomatology, global cognition, and the reward system. METHODS: The reward responsiveness of 63 patients with LLD and 58 healthy controls aged ≥60 years was assessed using the probabilistic reward learning task with an asymmetric reward schedule. RESULTS: Compared with healthy controls, patients with LLD displayed lower response bias and reward learning. Global cognition of all participants was positively correlated with response bias. In patients with LLD, anhedonia severity explained impaired reward learning. CONCLUSION: A deficit in reward processing is implicated in patients with LLD. Our findings suggest that executive dysfunction and anhedonia contribute to lower sensitivity to reward learning in patients with LLD.

Suicidal Risk in Older Patients with Depression During COVID-19 Pandemic: a Case-Control Study.

OBJECTIVES: To compare older adults with late-life depression (LLD) and healthy controls in terms of suicidal ideation during the COVID-19 pandemic, and to determine predictors of suicidal ideation. METHODS: Between March and April 2020, old adults diagnosed with major depressive disorder (single or recurrent episode) as defined by the DSM-5 were recruited from psychiatric clinics or inpatient wards, whereas 31 healthy older adults without a history of depression or other psychiatric illnesses were recruited from voluntary organisations or elderly community centres. Their depressive symptoms, perceived severity of the pandemic, perceived time spent on receiving related information, perceived health, levels of loneliness, perceived coping efficacy, suicidal ideation, and the level of symptomatic responses to a specific traumatic stressor in the past week were assessed. RESULTS: In total, 21 men and 43 women aged 61 to 89 years were interviewed through telephone by trained research assistants. Of them, 33 were older adults with LLD (cases) and 31 were healthy older adults (controls). Older people with LLD had a higher level of suicidal ideation than healthy controls, after controlling for the level of depression and medical comorbidity (F (1, 59) = 5.72, p = 0.020). Regression analyses showed that coping efficacy and loneliness accounted for a significant portion of the variance in suicidal ideation, and loneliness significantly predicted the level of stress. Mediation analyses reveal an indirect effect between group and suicidal ideation through coping efficacy (Z = 2.43, p = 0.015). CONCLUSIONS: Older people with LLD are at increased suicidal risk and require timely mental health support. Coping efficacy and loneliness are important predictors for suicidal ideation and stress.

Mindfulness-Based Cognitive Therapy for Late-Life Depression: a Randomised Controlled Trial.

BACKGROUND: Rumination and overgeneral autobiographical memory are dysfunctional cognitions commonly found in older adults with depression. The theoretical underpinnings of mindfulness-based cognitive therapy (MBCT) address the ruminative tendencies and the non-specific retrieval of autobiographical memories. This study aims to examine the efficacy and cognitive mechanisms of MBCT in older adults with active depressive symptoms. METHODS: 57 older adults (mean age, 70 years) with normal cognition and mild to moderate depressive symptoms were randomly allocated to either the MBCT group or the active control group for 8 weeks. The MBCT group consisted of eight 2-hour weekly sessions and a 7-hour full-day retreat, with different themes for each class, guided mindfulness exercises, feedback and discussion, homework review, and psychoeducation. The active control group comprised a 1-hour physical exercise and a standardised health education of the specific theme with group discussion (eg fall prevention, chronic pain). Participants were assessed before and after the 8-week intervention for four outcome measures: the Hamilton Depression Rating Scale (HAMD), the Ruminative Response Scale (RRS), the Autobiographical Memory Test (AMT), and the Mindful Attention Awareness Scale (MAAS). RESULTS: There was a significant reduction in severity of depressive symptoms (HAMD score) in both the MBCT group (F(1, 27) = 35.9, p < 0.001, η2 = 0.57) and the active control group (F(1, 28) = 9.29, p < 0.01, η2 = 0.24), but only the MBCT group showed substantial improvements in autobiographical memory specificity (AMT score), rumination (RRS score), and mindfulness (MAAS score). CONCLUSION: Although both MBCT and active control programme decrease the severity of depressive symptoms in older adults, only MBCT improves AMS, rumination, and mindfulness. Our findings provide empirical support for the theoretical underpinnings of MBCT. Older adults with more severe depression and more severe dysfunctional cognition may benefit more from the specific therapeutic effects of MBCT.

Cognitive Stimulation for Persons with Dementia: a Systematic Review and Meta-Analysis.

OBJECTIVE: We aim to provide an up-to-date systematic review and meta-analysis of the effects of cognitive stimulation (CS) on cognition, depressive symptoms, and quality of life in persons with dementia. Factors affecting the treatment effect were examined. METHODS: A literature search was performed on databases of MEDLINE, EMBASE, PsycINFO, CINAHL Plus, and Cochrane Library up to 7 March 2019. Only randomised controlled trials investigating the effects of CS in persons with dementia were included. The outcome measures were cognitive function, depressive symptoms, and quality of life. RESULTS: 20 randomised controlled trials with a total of 1251 participants (intervention group: 674; control group: 577) were included for meta-analysis. Most participants had mild to moderate dementia. CS had a significant positive small-to-moderate effect on cognition (Hedges's g = 0.313, p < 0.001). Heterogeneity of CS was low to moderate (Q=30.5854, df=19, p < 0.05, I2 = 37.877%). Inconclusive results were found for depressive symptoms and quality of life. CONCLUSION: CS has a significant positive effect on cognitive function, but its effect on depressive symptoms and quality of life was inconclusive. Future studies with more robust methodology establishing evidence of its efficacy are required.

Acute effects of mildly intoxicating levels of alcohol on left ventricular function in conscious dogs.

We assessed the effect of alcohol, before and after autonomic blockade, on left ventricular (LV) performance in conscious dogs. 10 animals were instrumented to determine LV volume from ultrasonic LV internal dimensions and measure LV pressure with a micromanometer. The animals were studied in the conscious state after full recovery from the operation. Blood alcohol was undetectable before and 67 +/- 14 mg/dl (mean +/- SD) at 20 min after alcohol administration. In response to alcohol, the LV systolic pressure was reduced slightly, the left ventricular end-diastolic pressure increased slightly. The maximum time derivative of LV pressure (dP/dtmax) and stroke volume were decreased. The end-systolic volume (VES), as well as effective arterial elastance, were significantly increased. There was no significant change in heart rate. Variably loaded pressure-volume loops were generated by acute caval occlusion before, immediately, and 20 min after the intravenous infusion of alcohol (0.2 g/kg). Three measures of LV performance were derived from these variably loaded pressure-volume loops: the end-systolic pressure-volume relation; the stroke work-end-diastolic volume relation; and maximum dP/dt-VED relation. The slopes of all three relations were significantly decreased in response to alcohol, and all three relations were shifted toward the right, indicating a depression of LV contractile performance. Similar, but greater depressions of LV performance with alcohol were observed following autonomic blockade. LV performance was restored by infusing dobutamine. We conclude that mildly intoxicating levels of alcohol (blood concentration less than 100 mg/dl) are capable of producing LV contractile depression in conscious animals, which is more marked after autonomic blockade. This suggests that patients with impaired LV function should avoid even small amounts of alcohol.

Upregulation of functional beta(3)-adrenergic receptor in the failing canine myocardium.

Altered expression and functional responses to cardiac beta(3)-adrenergic receptors (ARs) may contribute to progressive cardiac dysfunction in heart failure (CHF). We compared myocyte beta(3)-AR mRNA and protein levels and myocyte contractile, [Ca(2+)](i) transient, and Ca(2+) current (I(Ca,L)) responses to BRL-37344 (BRL, 10(-8) mol/L), a selective beta(3)-AR agonist, in 9 instrumented dogs before and after pacing-induced CHF. Myocytes were isolated from left ventricular myocardium biopsy tissues. Using reverse transcription-polymerase chain reaction, we detected beta(3)-AR mRNA from myocyte total RNA in each animal. Using a cloned canine beta(3)-AR cDNA probe and myocyte poly A(+) RNA, we detected a single band about 3.4 kb in normal and CHF myocytes. beta(3)-AR protein was detected by Western blot. beta(3)-AR mRNA and protein levels were significantly greater in CHF myocytes than in normal myocytes. Importantly, these changes were associated with enhanced beta(3)-AR-mediated negative modulation on myocyte contractile response and [Ca(2+)](i) regulation. Compared with normal myocytes, CHF myocytes had much greater decreases in the velocity of shortening and relengthening with BRL accompanied by larger reductions in the peak systolic [Ca(2+)](i) transient and I(Ca,L). These responses were not modified by pretreating myocytes with metoprolol (a beta(1)-AR antagonist) or nadolol (a beta(1)- and beta(2)-AR antagonist), but were nearly prevented by bupranolol or L-748,337 (beta(3)-AR antagonists). We conclude that in dogs with pacing-induced CHF, beta(3)-AR gene expression and protein levels are upregulated, and the functional response to beta(3)-AR stimulation is increased. This may contribute to progression of cardiac dysfunction in CHF.

Allopurinol enhances the contractile response to dobutamine and exercise in dogs with pacing-induced heart failure.

BACKGROUND: Superoxide (O(2)(-)) generated by enhanced xanthine oxidase (XO) activity may contribute to the increased myocardial oxidative stress in heart failure (CHF). Because blocking XO with allopurinol augments myofilament Ca(2+) sensitivity in reperfusion injury and CHF, we hypothesized that it may improve adrenergic inotropic responsiveness in CHF. METHODS AND RESULTS: We studied the effect of allopurinol on the contractile response to dobutamine and exercise in 7 chronically instrumented conscious dogs before and after producing CHF by rapid pacing. Left ventricular (LV) contractile performance was measured by the slopes of the LV end-systolic pressure-volume relation (E(ES)) and stroke work-end-diastolic volume relation (M(SW)). Before CHF, allopurinol produced no change in LV contractile performance and did not alter the response to dobutamine or exercise. After CHF, allopurinol produced significant (P:<0.05) increases in E(ES) (5.0+/-0.6 versus 3.3+/-0.6 mm Hg/mL) and M(SW). Dobutamine and allopurinol produced greater increases in E(ES) (5.4+/-0.6 versus 7.4+/-0.6 mm Hg/mL) and M(SW) (60.1+/-7.4 versus 73.7+/-4.4 mm Hg) than did dobutamine alone. After allopurinol, dP/dt(max), stroke volume, and M(SW) were higher during CHF exercise. LV diastolic pressures were lower during CHF exercise after allopurinol. CONCLUSIONS: Allopurinol has no discernable effects on LV contractile function or adrenergic responsiveness in normal, conscious animals. In pacing-induced CHF, however, allopurinol improves LV systolic function at rest and during adrenergic stimulation and exercise.

Functional effects of endogenous bradykinin in congestive heart failure.

OBJECTIVES: The purpose of this study was to determine the level and functional effects of endogenous bradykinin in congestive heart failure (CHF). BACKGROUND: There is experimental evidence that bradykinin is increased in several cardiac disease states. However, it is unknown whether plasma levels of bradykinin are elevated in CHF. Further, the cardiac and vascular responses to bradykinin in CHF are unclear. METHODS: The circulating levels of bradykinin and the effects of endogenous bradykinin were assessed in eight instrumented, conscious dogs both before and after pacing-induced CHF. RESULTS: Before CHF, the plasma bradykinin level was 53.1 +/- 12.4 pg/ml. Blocking endogenous bradykinin with HOE-140 (0.3 mg/kg), a specific bradykinin B2-receptor antagonist, produced no significant alterations in heart rate, left ventricular (LV) end-systolic pressure (Pes), total systemic resistance (TSR), the time constant of LV relaxation (tau) or the maximal rate of LV filling (dV/dt(max)). However, coronary blood flow was significantly reduced (p < 0.05). LV contractile performance measured by the slopes of pressure-volume relations was unaffected. After induction of CHF, the plasma bradykinin level increased to 234.2 +/- 19.4 pg/ml (p < 0.05). Blocking endogenous bradykinin with HOE-140 reduced coronary blood flow and produced significant increases in Pes and TSR, prolonged tau, decreased dV/dt(max) and elevated minimal LV pressure and mean left atrial pressure. Furthermore, the slopes of pressure-volume relations (p < 0.05) were decreased, indicating depressed contractility with HOE-140 after CHF. CONCLUSIONS: Before CHF, endogenous bradykinin results in coronary dilation but has no effect on systemic arterial vasodilation or cardiac performance. After CHF, endogenous bradykinin is significantly increased and, acting through B2-receptors, produces coronary and arterial vasodilation and improves LV relaxation and contractile performance. Thus, endogenous bradykinin may play an important role in preserving cardiovascular function in CHF.

Structural and functional analysis of the 3' untranslated region of bamboo mosaic potexvirus genomic RNA.

The secondary structure of a 170 nt transcript derived from a cDNA clone containing the 3' untranslated region of bamboo mosaic potexvirus (BaMV) with 32 adenine residues of the poly(A) tail, was investigated in solution by using enzymatic and chemical probes. Three consecutive stem-loops forming a cloverleaf-like structure (domain ABC) and a major stem-loop (domain D) containing a bulge and an internal loop were identified as connected to a previously identified pseudoknot domain (domain E) comprising at least 13 adenylate residues of the 3' poly(A) tail. The highly conserved hexamer nucleotides (ACc/uUAA) among potexviruses are located in loop D and the putative polyadenylation signal (AAUAAA) is located in the internal loop of domain D. Based on the data of the structural probing, a three-dimensional structure was modeled. Mutants with domain ABC deleted showed no detectable signal in protoplasts, while changes in domain D, except for the bulge deletion, showed interference of BaMV RNA accumulation in protoplasts. Mutants with disrupted stem D formation impaired BaMV accumulation. However, the mutant with compensatory mutations restored stem formation which could only improve the viral accumulation to 58 % that of the wild-type structure.

Haemodynamic changes in adrenaline-induced acute massive lung oedema.

During the production of adrenaline-induced acute massive lung oedema in the dog, plumonary arterial, pulmonary venous, systemic arterial, and bronchial arterial blood pressures all increase markedly. Pulmonary arterial and venous blood flows fall steeply after initial transient rises. Systemic arterial blood flow also declines, with or without an initial transient increase. The bronchial arterial blood flow shows an initial fall followed by a rise of late onset. The main determinant for the pathogenesis of adrenaline-induced lung oedema is apparently the enormously increased hydrostatic pressure in the pulmonary vascular bed.

Estimation of left ventricular elastance without altering preload or afterload in the conscious dog.

OBJECTIVE: The aim was to determine the slope (EES) of the left ventricular end systolic pressure-volume line (ESPVL) without altering preload or afterload in conscious dogs. METHODS: Dogs (n = 10) were instrumented to determine left ventricular volume from ultrasonic left ventricular internal dimensions, and to measure left ventricular pressure using a micromanometer. Studies were performed one to two weeks after instrumentation while the animals were conscious. ESPVL was determined from variably loaded left ventricular pressure-volume (P-V) loops generated by the vena caval occlusion. Contractile state was increased by intravenous dobutamine (8 micrograms.kg-1 x min-1) and decreased by intravenous verapamil (10 mg) given after autonomic blockade. From a single normally ejecting beat, we calculated EES-single beat (mm Hg.ml-1) as peak isovolumetric pressure (Pmax) minus end systolic pressure divided by stroke volume. Sunagawa's technique was used to estimate Pmax by fitting the pressure during the isovolumetric contraction and relaxation as: P(t) = 1/2 X Piso[1-cos(omega t+c)]+LVEDP, where Piso = peak isovolumetric developed pressure, LVEDP = left ventricular end diastolic pressure, c = constant accounting for variations in phase angle, and omega = 2 pi/T in which T is duration of contraction. RESULTS: After dobutamine, EES increased, from 8.9(SEM 0.8) to 12.5(1.0) mm Hg.ml-1 (p < 0.05), and EES-single beat increased from 9.1(0.9) to 12.0(1.4) mm Hg.ml-1 (p < 0.05). Conversely, after verapamil, EES decreased, from 11.1(1.2) to 6.3(1.1) mm Hg.ml-1, (p < 0.05), and EES-single beat also decreased, from 9.6(1.0) to 7.3(1.2) mm Hg.ml-1, (p < 0.05). CONCLUSIONS: EES calculated from one beat is similar to EES determined from variably loaded left ventricular loops and responds appropriately to inotropic stimulation. This technique provides a reasonable method to calculate EES from left ventricular pressure and stroke volume without altering preload or afterload.

Altered inotropic response of endothelin-1 in cardiomyocytes from rats with isoproterenol-induced cardiomyopathy.

OBJECTIVE: The positive inotropic effect of endothelin-1 (ET-1) on normal myocardial contraction may be altered in pathological states. The purpose of this study was to assess the direct effect of ET-1 on cardiomyocyte performance and its cellular mechanism in congestive heart failure (CHF). METHODS: We measured the plasma levels of ET-1 and compared the effects of ET-1 (10(-10)-10(-8) M) on contractile performance and the [Ca2+]i transient in the myocytes of left ventricles (LV) from 15 age-matched normal adult rats and 15 rats with isoproterenol (ISO)-induced CHF. RESULTS: With CHF, the plasma levels of ET-1 (19.7 +/- 6.3 vs. 4.1 +/- 0.5 fmol/ml, p < 0.05) were markedly elevated. In normal myocytes, superfusion of ET-1 caused significant increases in the systolic amplitude (SA, 8-16%) and the peak velocity of shortening (dL/dtmax, 20-35%; p < 0.01) without causing a change in the peak [Ca2+]i transient. In contrast, in myocytes from CHF rats, ET-1 produced significant reductions in SA (9-13%) and in the velocity of relengthening, dR/dtmax (10-14%; p < 0.05). The myocytes' dR/dtmax also decreased by 8-10% (p < 0.05). These changes were associated with a significant decrease in the peak [Ca2+]i transient (20-23%, p < 0.01). These responses to ET-1 were abolished by the incubation of myocytes with an ETA receptor antagonist (BQ123) or a protein kinase C (PKC) inhibitor (H-7 or staurosporine). CONCLUSION: ISO-induced CHF is associated with elevated plasma ET-1 and an altered cardiomyocyte response to ET-1. After CHF, ET-1 produces a direct depression of cardiomyocyte contractile performance that is associated with a significant decrease in the peak [Ca2+]i transient. These effects are likely to be mediated through ETA receptors and involve the PKC pathway.

Adrenaline-induced acute massive pulmonary oedema in the dog.

Pericardiotomy followed by intravenous injection of adrenaline (1 mg/kg body weight) provides a reliable method for the production of acute massive lung oedema in the dog. The lung wet weight: heart wet weight ratio is found to be the best assessment of the degree of lung oedema. A ratio greater than two represents massive lung oedema.

Effect of anti-inflammatory drugs on the production of tumour necrosis factor and lipopolysaccharide induced-mortality in mice.

Mice injected with viable Listeria monocytogenes or powdered Corynebacterium parvum and challenged with endotoxin released tumour necrosis factor (TNF) into the blood. However, the rate of mortality from endotoxin shock was high. Administration of the non-steroidal anti-inflammatory drugs acetylsalicylate, indomethacin and phenylbutazone protected the animals against the lethal effect of endotoxin without affecting the ability of animals to produce TNF. The significance of these observations are discussed.

Effect of combined treatment of anti-inflammatory drug and mannoheptulose on the production of tumour necrosis factor and endotoxin shock in mice.

The endotoxin shock induced in mice by injection of viable Listeria monocytogenes and challenged with endotoxin can be alleviated by combined administration of mannoheptulose with acetylsalicylate or sulindac. The ability of animals to secrete tumour necrosis factor into the blood was, however, not affected. The significance of these observations are discussed.

Endotoxin shock and tumour necrosis factor release in mannoheptulose-treated mice.

Administration of mannoheptulose partially protected mice infected with Listeria monocytogenes against the lethal effect of a subsequent endotoxin challenge. The ability of these animals to produce tumour necrosis factor was however unaffected. Mannoheptulose was observed to reverse the hypoglycaemic effect of endotoxin, possibly through inhibition of insulin secretion. The therapeutic significance of these observations is discussed.

Vascular versus myocardial effects of calcium antagonists.

As vascular smooth muscle tone and myocardial contractility both depend on calcium entry, the calcium antagonists are not only potent arterial vasodilators, but may also have important negative inotropic effects. For example, verapamil is nearly equipotent in reducing vascular smooth muscle tone and myocardial contraction in isolated tissue preparations. In contrast, felodipine has high vascular selectivity in such preparations, and drug concentrations required to depress myocardial contraction are more than 100 times greater than those required to relax vascular smooth muscle. In the isolated, isovolumetrically contracting canine left ventricle, clinically relevant concentrations of felodipine (14 nmol/L) produce coronary vasodilation and a mild positive inotropic response. Using left ventricular (LV) pressure-volume analysis, we evaluated a similar dose of felodipine (plasma drug concentration 16 nmol/L) in conscious dogs. Felodipine produced a 25mm Hg fall in arterial pressure and a 10% reduction in peripheral vascular resistance. There was no negative inotropic effect. Instead, myocardial contractile performance was slightly but significantly enhanced. These results were not altered by adrenergic blockade. Further studies in our laboratory showed that doses of amlodipine and nifedipine producing arterial vasodilation of a magnitude similar to that produced by felodipine had negative inotropic effects in the conscious dog. Only felodipine enhanced the rate of LV relaxation and the rate of early diastolic filling. Thus, felodipine was significantly more vasoselective than amlodipine and nifedipine. The direct inotropic effects of calcium antagonists are difficult to evaluate in clinical studies because of the load-dependence of most conventional measures of LV performance. However, no negative inotropic effects are clinically relevant doses of felodipine have been identified.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of left ventricular diastolic function from the pattern of left ventricular filling.

The pattern of left ventricular (LV) filling can be determined by Doppler echocardiography. Normally most LV filling occurs early in diastole, with some additional filling occurring during atrial systole, late in diastole. In the absence of mitral stenosis, three patterns of LV filling indicate progressively greater diastolic dysfunction: (1) Reduced early diastolic filling with a compensatory increase in importance of atrial filling, termed a pattern of "impaired relaxation;" (2) "pseudo-normalization" with most filling early in diastole but with rapid deceleration of mitral flow; and (3) "restricted filling" with almost all filling of the LV occurring very early in diastole in association with very rapid deceleration of mitral flow. A large, prolonged atrial regurgitant flow in the pulmonary veins also indicates impaired diastolic performance. The time for early filling deceleration is predominantly determined by LV stiffness: the shorter the deceleration time, the stiffer the LV. Patients with short deceleration time have a poor prognosis.

Coupling of the left ventricular and arterial system.

We investigated the coupling of the left ventricle (LV) and the arterial system in eight conscious dogs, instrumented to measure LV pressure and determine LV volume from three ultrasonically determined dimensions. The LV end-systolic pressure (PES)-volume (VES) relation was determined by caval occlusion. Its slope (EES) was compared to the arterial elastance (EA), determined as PES/stroke volume. At rest, with intact reflexes, EES/EA was 0.9 +/- 0.20. EES/EA was varied over a wide range (0.18-2.59) by the infusion of graded doses of phenylephrine and nitroprusside and dobutamine. Maximum LV SW, at constant inotropic state and end-diastolic volume, occurred when EES/EA = 0.99 +/- 0.15. However, SW was within 20% of its maximum value when EES/EA was between 0.56 and 2.29. As EES/EA decreased below 0.59, SW fell precipitously. The shape of the observed relation of SW to EES/EA was similar to that predicted by the theoretical consideration of linear LV PES-VES and arterial PES-stroke volume relations. We conclude that the LV and arterial system produce maximum SW at constant VED when EES and EA are equal; however, the relation of SW to EES/EA has a broad plateau.