Impaired Diastolic Relaxation Research Articles

Impaired Diastolic Function and Disruption of the Force-Frequency Relationship in the Right Ventricle of Newborn Pigs Resuscitated with 100% Oxygen

Background: Resuscitation with 100% oxygen increases oxidative stress and is detrimental for organ function. Objective: To study the effects of resuscitation with 100% oxygen compared to room-air on myocardial function. Methods: Twenty-eight newborn pigs underwent global hypoxia (8% oxygen/N₂) until base excess reached –20 mmol/l. The animals were randomized into two groups and resuscitated with either 100% or room air for 30 min. Myocardial tissue Doppler velocities and acceleration of the mitral and tricuspid valve annuli during systole and diastole were assessed before global hypoxia and after resuscitation together with troponin I. Results: Peak early diastolic velocity (E′) and acceleration (pEac) in the septum and pEac in the lateral tricuspid valve annulus were lower after resuscitation with 100% oxygen, suggesting impaired diastolic relaxation in the right ventricle. Lower systolic velocities and acceleration in the right ventricle relative to heart rate indicate disruption of the right ventricular force-frequency relationship after resuscitation with 100% oxygen. Troponins were higher in the 100% oxygen group, suggesting increased myocardial damage in this group. Conclusion: Resuscitation with 100% oxygen compared to room air induces diastolic dysfunction, disrupts the systolic force-frequency relationship and increases myocardial damage in the newborn pig.

In-treatment stroke volume predicts cardiovascular risk in hypertension

To evaluate whether lower stroke volume during antihypertensive treatment is a predictor of cardiovascular events independent of left ventricular geometric pattern. The association between left ventricular stroke volume and combined cardiovascular death, stroke and myocardial infarction, the prespecified primary study endpoint, was assessed in Cox regression analysis using data from baseline and annual follow-up visits in 855 patients during 4.8 years of randomized losartan-based or atenolol-based treatment in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echocardiography substudy. During follow-up, a total of 91 primary endpoints occurred. At baseline, lower left ventricular stroke volume was associated with smaller body size, female sex, lower left ventricular mass and stress-corrected midwall shortening, higher relative wall thickness and total peripheral resistance, more concentric left ventricular geometry and impaired diastolic relaxation (all P < 0.01). Baseline stroke volume did not predict outcome. However, in time-varying multivariable Cox regression analysis, lower in-treatment left ventricular stroke volume indexed for height was associated with higher risk of cardiovascular events {hazard ratio 1.69 per 1 SD (6 ml/m) lower stroke volume [95% confidence interval (CI) 1.35-2.11], P < 0.001} independent of in-treatment left ventricular mass and concentric geometry and in a secondary model also independent of stress-corrected midwall shortening, impaired diastolic relaxation, heart rate, new-onset atrial fibrillation and study treatment [hazard ratio 1.46 per 1 SD (6 ml/m) lower stroke volume (95% CI 1.13-1.88)]. Assessment of in-treatment left ventricular stroke volume may reflect cardiac and vascular remodeling and impairment and, hence, adds information on cardiovascular risk in treated hypertensive patients beyond assessment of left ventricular structure alone. NCT 00338260.

Hemodynamic Disturbances and Activation of Lipid Peroxidation in the Pathogenesis of Acute Myocardial Injury Induced by Propranolol in Toxic Doses

We studied the dose-dependent cardiotoxic effect of propranolol. Intraperitoneal injection of propranolol in doses of 1 and 2 mg/100 g body weight produced a potent effect on central hemodynamics and myocardial contractility, impaired diastolic relaxation, and caused damage to cardiomyocyte membranes due to activation of free radical oxidation.

Atrial Dilation and Altered Function Are Mediated by Age and Diastolic Function But Not Before the Eighth Decade

This study investigated changes in left atrial (LA) volumes and phasic atrial function, by deciles, with normal aging. LA volume increase is a sensitive independent marker for cardiovascular disease and adverse outcomes. To use this variable more effectively as a marker of pathology and a gauge of outcome, physiological changes due to aging alone need to be quantitated. A detailed transthoracic echocardiogram was performed in 220 normal subjects; 89 (41%) were male and their age ranged from 20 to 80 years (mean 45 ± 17 years). Maximum (end-ventricular systole), minimum (end-ventricular diastole), and pre-a-wave volumes were measured using the biplane method of disks. LA filling, passive emptying, conduit and active emptying volumes, and fractions were calculated. Transmitral inflow, pulmonary vein flow, and pulsed-wave Doppler tissue imaging parameters were measured as expressions of left ventricular diastolic function. For purposes of analysis, subjects were divided by age deciles. LA indexed maximum (0.05 ml/m(2) per year) and minimum (0.06 ml/m(2) per year) volume increased with age but only became significant in the eighth decade (26.0 ± 6.3 ml/m(2), p = 0.02, and 13.5 ± 3.9 ml/m(2), respectively; p < 0.001). Impaired left ventricular diastolic relaxation was apparent in decade 6 and was associated with a shift in phasic LA volumes so that LA expansion index and passive emptying decreased with increasing age, whereas active emptying volume increased. In normal healthy subjects, LA indexed volumes remain nearly stable until the eighth decade when they increase significantly. Therefore, an increase in LA size that occurs before the eighth decade is likely to represent a pathological change. Changes in phasic atrial volumes develop earlier consequent to age-related alteration in LV diastolic relaxation.

Levosimendan improves cardiac function and survival in rats with angiotensin II-induced hypertensive heart failure

Calcium-sensitizing agents improve cardiac function in acute heart failure; however, their long-term effects on cardiovascular mortality are unknown. We tested the hypothesis that levosimendan, an inodilator that acts through calcium sensitization, opening of ATP-dependent potassium channels and phosphodiesterase III inhibition, improves cardiac function and survival in double transgenic rats harboring human renin and angiotensinogen genes (dTGRs), a model of angiotensin II (Ang II)-induced hypertensive heart failure. Levosimendan (1 mg kg(-1)) was administered orally to 4-week-old dTGRs and normotensive Sprague-Dawley rats for 4 weeks. Untreated dTGRs developed severe hypertension, cardiac hypertrophy, heart failure with impaired diastolic relaxation, and exhibited a high mortality rate at the age of 8 weeks. Levosimendan did not decrease blood pressure and did not prevent cardiac hypertrophy. However, levosimendan improved systolic function, decreased cardiac atrial natriuretic peptide mRNA expression, ameliorated Ang II-induced cardiac damage and decreased mortality. Levosimendan did not correct Ang II-induced diastolic dysfunction and did not influence heart rate. In a separate survival study, levosimendan increased dTGR survival by 58% and median survival time by 27% (P=0.004). Our findings suggest that levosimendan ameliorates Ang II-induced hypertensive heart failure and reduces mortality. The results also support the notion that the effects of levosimendan in dTGRs are mediated by blood pressure-independent mechanisms and include improved systolic function and amelioration of Ang II-induced coronary and cardiomyocyte damage.

Uncoupled Cardiac Nitric Oxide Synthase Mediates Diastolic Dysfunction

Heart failure with preserved ejection fraction is 1 consequence of hypertension and is caused by impaired cardiac diastolic relaxation. Nitric oxide (NO) is a known modulator of cardiac relaxation. Hypertension can lead to a reduction in vascular NO, in part because NO synthase (NOS) becomes uncoupled when oxidative depletion of its cofactor tetrahydrobiopterin (BH(4)) occurs. Similar events may occur in the heart that lead to uncoupled NOS and diastolic dysfunction. In a hypertensive mouse model, diastolic dysfunction was accompanied by cardiac oxidation, a reduction in cardiac BH(4), and uncoupled NOS. Compared with sham-operated animals, male mice with unilateral nephrectomy, with subcutaneous implantation of a controlled-release deoxycorticosterone acetate pellet, and given 1% saline to drink were mildly hypertensive and had diastolic dysfunction in the absence of systolic dysfunction or cardiac hypertrophy. The hypertensive mouse hearts showed increased oxidized biopterins, NOS-dependent superoxide production, reduced NO production, and dephosphorylated phospholamban. Feeding hypertensive mice BH(4) (5 mg/d), but not treating with hydralazine or tetrahydroneopterin, improved cardiac BH(4) stores, phosphorylated phospholamban levels, and diastolic dysfunction. Isolated cardiomyocyte experiments revealed impaired relaxation that was normalized with short-term BH(4) treatment. Targeted cardiac overexpression of angiotensin-converting enzyme also resulted in cardiac oxidation, NOS uncoupling, and diastolic dysfunction in the absence of hypertension. Cardiac oxidation, independently of vascular changes, can lead to uncoupled cardiac NOS and diastolic dysfunction. BH(4) may represent a possible treatment for diastolic dysfunction.

Segmental Differences of Impaired Diastolic Relaxation Following Cardiopulmonary Bypass Surgery in Children: A Tissue Doppler Study

Impaired myocardial relaxation is an important aftereffect of cardiopulmonary bypass (CPB). Infants with their immature calcium metabolism may be particularly vulnerable. However, it has been difficult to quantitate diastolic dysfunction clinically. This study used tissue Doppler to measure regional diastolic myocardial velocities in 31 pediatric patients undergoing open heart surgery. Color tissue Doppler images were acquired in the operating room before and 8 and 24 h post CPB surgery. Early (E) and atrial (A) diastolic velocities were determined. Long axis motion was assessed from apical views near the mitral and tricuspid rings and radial wall motion from the parasternal view. The study included 31 children aged 3.6 +/- 4.4 years (6 days to 16 years), with a mean weight of 14.7 +/- 13.7 kg and body surface area of 0.59 +/- 0.35 m(2). Tissue Doppler analysis of regional wall motion revealed abnormal left ventricle (LV) and right ventricle (RV) diastolic relaxation in the early postoperative phase after CPB. Initially, all segments were significantly altered, but by 24 h, regional differences became apparent: LV radial wall motion was recovered, while longitudinal fibers in LV and RV appeared to be less resilient. RV myocardial mechanics were most abnormal. Tissue Doppler analysis may deepen our understanding of myocardial recovery and offers a sensitive tool to compare different cardioprotective strategies.

CARDIOPROTECTION BY HYDROGEN SULFIDE

CARDIOPROTECTION BY HYDROGEN SULFIDE

Systolic Heart Failure in a Patient With Hypertrophic Obstructive Cardiomyopathy

Systolic Heart Failure in a Patient With Hypertrophic Obstructive Cardiomyopathy

Influence of Ventricular Pressure Drop on Mitral Annulus Dynamics Through the Process of Vortex Ring Formation

Several studies have suggested that the mitral annulus displacement and velocity in early diastole can be used as indicators of diastolic performance. The peak velocity of the mitral annulus away from the LV apex during early diastole, which indicates the rate of longitudinal expansion of the LV, is reduced in patients with impaired diastolic relaxation. With the intention of relating the trans-mitral flow to mitral annulus plane dynamics, we measured mitral annulus recoil force for different valve sizes, while applying an exponential pressure drop in a simplified model of the ventricle. The temporal changes in diameter of the valve during rapid filling phase were also considered. The process of ventricular vortex formation was studied together with the measurement of mitral annulus recoil force within different pressure drop conditions. Matching the vorticity contour plots with the recoil force measurements resulted in the fact that the magnitude of recoil is maximal once the vortex ring is about to pinch off, regardless of the valve size or the characteristics of ventricular pressure drop. This study showed that the mitral annulus recoil is maximal once occurs at the vortex formation time ranging from 3.5 to 4.5. It was also shown that the presence of leaflets would dissipate the annulus recoil force.

The left ventricle and hemodynamic patterns in essential hypertension

Hemodynamic patterns in hypertensive patients by radionuclide techniques and tomographic gamma camera were evaluated. In younger hypertensive patients, the hyperkinetic state reflected an increase in heart rate and, consequently, an increased cardiac index and left ventricular ejection fraction (LVEF). Older hypertensive patients, however, showed a different hemodynamic pattern, with reduced systolic and diastolic function at rest compared with normotensive elderly people, and marked depression of cardiac systolic and diastolic reserve during exercise. They also showed strikingly higher hyperresistance and reduced peripheral perfusion. These hemodynamic differences need to be taken into account when considering antihypertensive treatment. In a study in 106 elderly hypertensive patients, treatment with four different antihypertensive drugs produced a significant decrease in total peripheral resistance and blood pressure, together with a reduction in left ventricular (LV) afterload and an increase in cardiac output and LVEF (tending towards normal values). The LV peak filling rate was also increased and evaluation of systolic and diastolic cardiac reserve during exercise showed positive changes in cardiac performance. Left ventricular hyperthropy (LVH) is a powerful predictor of cardiac events. Long-term increases in BP predispose to LVH, impaired diastolic relaxation and, ultimately, ventricular dysfunction. A reduction in LVH produces a number of different beneficial effects. Coronary flow reserve was evaluated in hypertensive patients. Coronary flow reserve was highly impaired in comparison with normotensive controls, and increases in arteriolar wall thickness, collagen content and diastolic dysfunction were also noted. A marked improvement in coronary flow reserve in patients who received antihypertensive therapy was confirmed.

Hyperhomocysteinemic Diabetic Cardiomyopathy: Oxidative Stress, Remodeling, and Endothelial-Myocyte Uncoupling

Accumulation of oxidized-matrix (fibrosis) between the endothelium (the endothelial cells embedded among the myocytes) and cardiomyocytes is a hallmark of diabetes mellitus and causes diastolic impairment. In diabetes mellitus, elevated levels of homocysteine activate matrix metalloproteinase and disconnect the endothelium from myocytes. Extracellular matrix functionally links the endothelium to the cardiomyocyte and is important for their synchronization. However, in diabetes mellitus, a disconnection is caused by activated metalloproteinase, with subsequent accumulation of oxidized matrix between the endothelium and myocyte. This contributes to endothelial-myocyte uncoupling and leads to impaired diastolic relaxation of the heart in diabetes mellitus. Elevated levels of homocysteine in diabetes are attributed to impaired homocysteine metabolism by glucose and insulin and decreased renal clearance. Homocysteine induces oxidative stress and is inversely related to the expression of peroxisome proliferators activated receptor (PPAR). Several lines of evidence suggest that ablation of the matrix metalloproteinase (MMP-9) gene ameliorates the endothelial-myocyte uncoupling in diabetes mellitus. Homocysteine competes for, and decreases the PPARgammaactivity. In diabetes mellitus, endothelial-myocyte uncoupling is associated with matrix metalloproteinase activation and decreased PPARgamma activity. The purpose of this review is to discuss the role of endothelial-myocyte uncoupling in diabetes mellitus and increased levels of homocysteine, causing activation of latent metalloproteinases, decreased levels of thioredoxin and peroxiredoxin, and cardiac tissue inhibitor of metalloproteinase (CIMP) in response to antagonizing PPARgamma.

Relation of impaired left ventricular filling to systolic midwall mechanics in hypertensive patients with normal left ventricular systolic chamber function: The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study

Background Patients with hypertensive left ventricular (LV) hypertrophy commonly have diastolic dysfunction with preserved LV ejection fraction. LV systolic midwall shortening (MWS) may be impaired in hypertensive patients with normal LV ejection fraction. However, it is unclear whether impaired LV filling is related to depressed systolic midwall mechanics. Methods Echocardiographic measures of LV diastolic filling and systolic performance were compared in 632 unmedicated patients with stage II or III hypertension and LV hypertrophy determined by electrocardiogram, with LV ejection fraction >55% and <2+ mitral regurgitation. Results Stress-corrected LV MWS, an index of myocardial contractility, was lower in patients with abnormal as opposed to normal LV filling patterns (98% ± 12% vs 102% ± 10%, P < .001) and in patients with prolonged as opposed to normal isovolumic relaxation time (IVRT) (98% ± 13% vs 101% ± 12%, P = .014). Stress-corrected MWS was <85% of predicted levels in more patients with abnormal LV filling patterns (11.8% vs 6.3%) or with long IVRT (≥105 msec) (34% vs 21%, both P < .05). In regression analyses, lower stress-corrected MWS and higher LV mass were independent correlates of longer IVRT, while lower stress-corrected MWS was the only independent correlate of prolonged mitral valve deceleration time ( P = .017). Higher LV mass had strong, statistically independent relationships to longer IVRT (by 0.3 g/msec) and decreased stress-corrected MWS (by 0.5 g/%; both P < .0001), independent of body size and age. Conclusion In patients with moderate hypertension and target organ damage who have normal LV ejection fraction, impaired early diastolic LV relaxation (abnormal E/A ratio, prolonged IVRT and deceleration time) is associated with impaired LV systolic midwall mechanics independent of higher LV mass.

Circulating tissue inhibitor of metalloproteinase-1 elevation correlates with impaired diastolic relaxation in patients with hypertension

P-374 Key Words: Tissue Inhibitor of Metalloproteinase, Diastolic Dysfunction, Hypertension

Glycogen Synthase Kinase-3β Regulates Growth, Calcium Homeostasis, and Diastolic Function in the Heart

Glycogen synthase kinase (GSK) 3beta is a negative regulator of stress-induced cardiomyocyte hypertrophy. It is not clear, however, if GSK-3beta plays any role in regulating normal cardiac growth and cardiac function. Herein we report that a transgenic mouse expressing wild type GSK-3beta in the heart has a dramatic impairment of normal post-natal cardiomyocyte growth as well as markedly abnormal cardiac contractile function. The most striking phenotype, however, is grossly impaired diastolic relaxation, which leads to increased filling pressures of the left ventricle and massive atrial enlargement. This is due to profoundly abnormal calcium handling, leading to an inability to normalize cytosolic [Ca2+] in diastole. The alterations in calcium handling are due at least in part to direct down-regulation of the sarcoplasmic reticulum calcium ATPase (SERCA2a) by GSK-3beta, acting at the level of the SERCA2 promoter. These studies identify GSK-3beta as a regulator of normal growth of the heart and are the first of which we are aware, to demonstrate regulation of expression of SERCA2a, a critical determinant of diastolic function, by a cytosolic signaling pathway, the activity of which is dynamically modulated. De-regulation of GSK-3beta leads to severe systolic and diastolic dysfunction and progressive heart failure. Because down-regulation of SERCA2a plays a central role in the diastolic and systolic dysfunction of patients with heart failure, these findings have potential implications for the therapy of this disorder.

1142-186 Elevated levels of circulating tissue inhibitor of metalloproteinase-1 correlate with impaired diastolic relaxation in hypertension: Implications for diastolic heart failure

1142-186 Elevated levels of circulating tissue inhibitor of metalloproteinase-1 correlate with impaired diastolic relaxation in hypertension: Implications for diastolic heart failure

Can angiotensin II type 2 receptors have deleterious effects in cardiovascular disease? Implications for therapeutic blockade of the renin-angiotensin system.

The renin–angiotensin system (RAS) plays a major role in regulating the cardiovascular system, and disorders of the RAS contribute largely to the pathophysiology of hypertension, renal diseases, and chronic heart failure. Two subtypes of angiotensin II (Ang II) receptors have been defined on the basis of their differential pharmacological and biochemical properties: Ang II type 1 receptors (AT1), which are involved in most of the well-known physiological effects of Ang II, and Ang II type 2 receptors (AT2), which have a less well-defined role but appear capable of counterbalancing some of the effects of AT1 stimulation. The 2 receptors, both of which belong to the superfamily of G-protein–coupled receptors, are believed to have different signaling pathways and different functions.1 AT1 transactivates growth pathways and mediates major Ang II effects such as vasoconstriction, increased cardiac contractility, renal tubular sodium reabsorption, cell proliferation, vascular and cardiac hypertrophy, inflammatory responses, and oxidative stress. AT2 is believed to induce essentially opposite effects, including vasodilation and antigrowth and antihypertrophic effects,1–3 and to play a significant role in blood pressure (BP) regulation.4 The 2 major pharmacological inhibitors of the RAS, which are now important elements in the treatment of hypertension and cardiovascular disease, are ACE inhibitors and angiotensin receptor blockers (ARBs). These 2 classes of drugs have different effects on the RAS: suppression of Ang II production by ACE inhibitors reduces activation of both Ang II receptor subtypes, whereas ARBs preferentially block AT1 and leave AT2 unopposed. Long-term administration of ARBs results in a several-fold increase in plasma Ang and thus a possible overstimulation of AT2. It is generally accepted that the effects of stimulation of AT2 on the cardiovascular system are beneficial and that no harm would result from increased activation of …

ANP but not BNP reflects early left diastolic dysfunction in type 1 diabetics with myocardial dysinnervation.

We investigated whether plasma concentrations of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) reflect impaired diastolic relaxation or its improvement after ACE inhibition. 7 long-term Type 1 diabetic patients with normal systolic but impaired diastolic function and with sympathetic myocardial dysinnervation and 10 controls were included. Exercise tolerance and maximal O 2 uptake were evaluated by bicycle exercise prior to the study. ANP, BNP and norepinephrine/epinephrine (NE/E) were determined at baseline and at 80 % .VO2 max workload and after recovery, before and following 12 weeks of treatment with fosinopril (10 mg/d). Isovolumetric relaxation time (IVRT) and A/E wave ratio were increased by 26.7 +/- 11.5 % and 54.4 +/- 26.1 % in diabetic patients as compared to controls, respectively (p < 0.02). After 12 weeks of fosinopril treatment, no differences in IVRT or A/E wave ratio were detectable between groups. ANP was enhanced in Type 1 diabetes as compared to controls (baseline: 9.2 +/- 3.0 vs. 4.5 +/- 1.1; exercise: 22.4 +/- 7.7 vs. 7.9 +/- 1.2; recovery: 20.3. +/- 4.6 vs. 9.5 +/- 2.0 fmol/ml, p < 0.02). Fosinopril treatment abolished any differences between groups. BNP plasma levels did not differ between groups and no exercise dependent changes were observed. NE- and E-increase was greater at 80 % .VO2 max work load in Type 1 diabetes than in controls (p < 0.05). Again, fosinopril abolished differences between groups. In Type 1 diabetes, impaired diastolic function is associated with elevated ANP and catecholamine plasma levels that are normalized after ACE inhibition. Thus, ANP but not BNP appears to be a sensitive biochemical marker for early diastolic dysfunction in Type 1 diabetes.

Decreased expression of myocardial eNOS and caveolin in dogs with hypertrophic cardiomyopathy.

Because nitric oxide (NO) regulates cardiac and vessel contraction, we compared the expression and activity of the endothelial NO synthase (eNOS) and caveolin, which tonically inhibits eNOS in normal and hypertrophic cardiomyopathic hearts. NOS activity (L-[(3)H]citrulline formation), eNOS immunostaining, and caveolin abundance were measured in heart tissue of 23 mongrel dogs before and at 3 and 7 wk of perinephritic hypertension (PHT). Hemodynamic parameters in vivo and endothelial NO-dependent relaxation of macro- and coronary microvessels in vitro were assessed in the same animals. eNOS immunostaining and total calcium-dependent NOS activity decreased at 7 wk in all four heart cavities (in left ventricle, from 17.0 +/- 1.3 to 0.2 +/- 0.2 fmol. min(-1). mg protein(-1), P < 0.001). Caveolin-1 and -3 also decreased in PHT dog hearts. Accordingly, basal vascular tone was preserved, but maximal endothelial NO-dependent relaxation was impaired in all vessels from 7-wk PHT dogs. The latter had preserved systolic function but impaired diastolic relaxation [relaxation time constant (T(1)), 25.1 +/- 0.9 vs. 22.0 +/- 1 ms in controls; P < 0.05]. Peripheral infusion of the NOS inhibitor N(G)-nitro-L-arginine methyl ester increased mean aortic pressure in both groups and reduced diastolic (T(1), 31.9 +/- 1.4 ms) and systolic function in PHT dogs (DP40, 47.5 +/- 2.5 vs. 59.4 +/- 3.8 s(-1) in control animals). In conclusion, both eNOS and caveolin proteins are decreased in the hypertrophic hearts of PHT dogs. This is associated with altered maximal (but not basal) vascular relaxation and impaired diastolic function. Further degradation of cardiac function after NOS inhibition suggests a critical role of residual NOS activity, probably supported by the concurrent downregulation of caveolin.

Effects of epinephrine on the myocardial performance and haemodynamics of the isolated rat heart during moderate hypothermia — importance of calcium homeostasis

Controversies exist concerning myocardial performance in hypothermia. We have studied the effects of epinephrine on myocardial function at various calcium concentrations in moderate hypothermia (28°C) and normothermia (37°C) using an isolated antegrade perfused rat heart. The maximum pressure velocity (d P/d t max) developed was significantly higher in normothermia compared with hypothermia and was improved by the addition of calcium in both circumstances. Peak negative pressure velocity (d P/d t min) was significantly higher at 37°C compared with 28°C, and was increased by the addition of calcium in normothermia; in contrast to hypothermia, in which no change of d P/d t min was observed. A reduction in cardiac output and stroke volume by hypercalcaemia was observed in hypothermia. The addition of epinephrine improved d P/d t max and d P/d t min, but had a depressive effect on stroke volume and cardiac output at normal and elevated calcium concentrations. Myocardial efficiency was significantly higher during hypothermia compared with normothermia, but was impaired by epinephrine during hypothermia. The variable or even paradoxical effects of epinephrine suggest the need for careful haemodynamic monitoring and determination of calcium levels in hypothermia. The impairment of myocardial performance may be explained by impaired diastolic relaxation and calcium overload.