Rosiglitazone treatment improves cardiac efficiency in hearts from diabetic mice.

Isolated perfused hearts from type 2 diabetic (db/db) mice show impaired ventricular function, as well as altered cardiac metabolism. Assessment of the relationship between myocardial oxygen consumption (MVO(2)) and ventricular pressure-volume area (PVA) has also demonstrated reduced cardiac efficiency in db/db hearts. We hypothesized that lowering the plasma fatty acid supply and subsequent normalization of altered cardiac metabolism by chronic treatment with a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist will improve cardiac efficiency in db/db hearts. Rosiglitazone (23 mg/kg body weight/day) was administered as a food admixture to db/db mice for five weeks. Ventricular function and PVA were assessed using a miniaturized (1.4 Fr) pressure-volume catheter; MVO(2) was measured using a fibre-optic oxygen sensor. Chronic rosiglitazone treatment of db/db mice normalized plasma glucose and lipid concentrations, restored rates of cardiac glucose and fatty acid oxidation, and improved cardiac efficiency. The improved cardiac efficiency was due to a significant decrease in unloaded MVO(2), while contractile efficiency was unchanged. Rosiglitazone treatment also improved functional recovery after low-flow ischemia. In conclusion, the present study demonstrates that in vivo PPARgamma-treatment restores cardiac efficiency and improves ventricular function in perfused hearts from type 2 diabetic mice.

Reduced coronary reserve in response to short-term ischaemia and vasoactive drugs in ex vivo hearts from diabetic mice.

AIM: The aim of the present study was to compare the coronary flow (CF) reserve of ex vivo perfused hearts from type 2 diabetic (db/db) and non-diabetic (db/+) mice. METHODS: The hearts were perfused in the Langendorff mode with Krebs-Henseleit bicarbonate buffer (37 degrees C, pH 7.4) containing 11 mmol L(-1) glucose as energy substrate. The coronary reserve was measured in response to three different interventions: (1) administration of nitroprusside (a nitric oxide donor), (2) administration of adenosine and (3) production of reactive hyperaemia by short-term ischaemia. RESULTS: Basal CF was approximately 15% lower in diabetic when compared with non-diabetic hearts (2.1 +/- 0.1 vs. 2.6 +/- 0.2 mL min(-1)). The maximum increase in CF rate in response to sodium nitroprusside and adenosine was significantly lower in diabetic (0.6 +/- 0.1 and 0.9 +/- 0.1 mL min(-1) respectively) than in non-diabetic hearts (1.2 +/- 0.1 and 1.4 +/- 0.1 mL min(-1) respectively). Also, there was a clear difference in the rate of return to basal CF following short-term ischaemia between diabetic and non-diabetic hearts. Thus, basal tone was restored 1-2 min after the peak hyperaemic response in non-diabetic hearts, whereas it took approximately 5 min in diabetic hearts. CONCLUSION: These results show that basal CF, as well as the CF reserve, is impaired in hearts from type 2 diabetic mice. As diabetic and non-diabetic hearts were exposed to the same (maximum) concentrations of NO or adenosine, it is suggested that the lower coronary reserve in type 2 diabetic hearts is, in part, because of a defect in the intracellular pathways mediating smooth muscle relaxation.

Cardiovascular effects of epinephrine during rewarming from hypothermia in an intact animal model.

Rewarming from accidental hypothermia is often complicated by "rewarming shock," characterized by low cardiac output (CO) and a sudden fall in peripheral arterial pressure. In this study, we tested whether epinephrine (Epi) is able to prevent rewarming shock when given intravenously during rewarming from experimental hypothermia in doses tested to elevate CO and induce vasodilation, or lack of vasodilation, during normothermia. A rat model designed for circulatory studies during experimental hypothermia and rewarming was used. A total of six groups of animals were used: normothermic groups 1, 2, and 3 for dose-finding studies, and hypothermic groups 4, 5, and 6. At 20 and 24 degrees C during rewarming, group 4 (low-dose Epi) and group 5 (high-dose Epi) received bolus injections of 0.1 and 1.0 microg Epi, respectively. At 28 degrees C, Epi infusion was started in groups 4 and 5 with 0.125 and 1.25 microg/min, respectively. Group 6 served as saline control. After rewarming, both CO and stroke volume were restored in group 4, in contrast to groups 5 and 6, in which both CO and stroke volume remained significantly reduced (30%). Total peripheral resistance was significantly higher in group 5 during rewarming from 24 to 34 degrees C, compared with groups 4 and 6. This study shows that, in contrast to normothermic conditions, Epi infused during hypothermia induces vasoconstriction rather than vasodilation combined with lack of CO elevation. The apparent dissociation between myocardial and vascular responses to Epi at low temperatures may be related to hypothermia-induced myocardial failure and changes in temperature-dependent adrenoreceptor affinity.

Measurement of coronary flow reserve in isolated hearts from mice.

AIM: Langendorff-perfused murine hearts are increasingly used in cardiovascular research, but coronary cardiovascular haemodynamics vary considerably from one research group to another. The aim of this study was to establish an isolated, retrogradely perfused mouse heart preparation for the simultaneous measurement of left ventricular haemodynamics and of coronary flow (CF). METHODS: Heart rate was controlled by right atrial pacing (480 beats min(-1)) and heart temperature was kept constant. Accurate flow values of <0.5 mL min(-1) could be determined, and this methodology was then used to study the stability of this preparation, as well as coronary response to vasoactive drugs and to short-term ischaemia. RESULTS: The CF and maximum systolic pressure were well maintained over a 2-h perfusion period, both showing a 10% decline per hour. Sodium-nitroprusside (endothelium-independent) and adenosine (endothelium-dependent) increased CF relatively modest (30-50% above baseline values). Short-term no-flow ischaemia caused a transient 40-50% increase in CF on reperfusion. Peak reflow occurred approximately 15 s after start of reperfusion and flow returned to baseline during the following 1-2 min. Increased coronary blood flow following infusion of vasoactive drugs (nitroprusside or adenosine) or short-term ischaemia were associated with minor changes in ventricular pressure development. CONCLUSIONS: Blood flow and haemodynamics can readily be determined in this isolated perfused mouse heart model, but CF reserve is relatively small, compared with blood-perfused organs.

Postischemic mechanoenergetic inefficiency is related to contractile dysfunction and not altered metabolism.

Mechanoenergetic inefficiency in postischemic nonnecrotic myocardium may partly be explained by an increased fatty acid (FA) oxidation rate. In the present study, left ventricular (LV) postischemic energy transfer was characterized in 10 intact anesthetized pigs. The LV was stunned by 11 brief left main coronary artery occlusions/reperfusions (20-min accumulated ischemia). Seven pigs served as time controls. The relationship between myocardial oxygen consumption (MVO(2)) and LV pressure-volume area (PVA) was assessed. [(14)C]glucose and [(3)H]oleate markers were used to discriminate between glucose and FA consumption. In stunned hearts, severe postischemic dysfunction was observed, and contractile efficiency was reduced (increased MVO(2)-PVA slope, P = 0.001). Unloaded (nonmechanical) MVO(2) was not affected by ischemia. We observed only a small transient increase in FA preference and conclude that the contribution from increased FA utilization to postischemic mechanoenergetic inefficiency is insignificant. Disrupted postischemic chemical-to-mechanical energy transfer in vivo is, therefore, related to inefficient energy utilization in the contractile apparatus.

[Chronic heart failure--suggestion to a management program]. / Kronisk hjertesvikt--forslag til handlingsprogram.

In 1994, a Norwegian programme for diagnosis and treatment of chronic heart failure was published. Recently the American College of Cardiology, the American Heart Association and the Task Force on Heart Failure of the European Society of Cardiology have published similar guidelines. In this article, the Working Group on Heart Failure of the Norwegian Society of Cardiology presents an updated programme for evaluation and management of patients with chronic heart failure.

Left ventricular dysfunction following rewarming from experimental hypothermia.

This study was aimed at elucidating whether ventricular hypothermia-induced dysfunction persisting after rewarming the unsupported in situ dog heart could be characterized as a systolic, diastolic, or combined disturbance. Core temperature of 8 mongrel dogs was gradually lowered to 25 degreesC and returned to 37 degreesC over a period of 328 min. Systolic function was described by maximum rate of increase in left ventricular (LV) pressure (dP/dtmax), relative segment shortening (SS%), stroke volume (SV), and the load-independent contractility index, preload recruitable stroke work (PRSW). Diastolic function was described by the isovolumic relaxation constant (tau) and the LV wall stiffness constant (Kp). Compared with prehypothermic control, a significant decrease in LV functional variables was measured at 25 degreesC: dP/dtmax 2,180 +/- 158 vs. 760 +/- 78 mmHg/s, SS% 20.1 +/- 1.2 vs. 13.3 +/- 1.0%, SV 11.7 +/- 0.7 vs. 8.5 +/- 0.7 ml, PRSW 90.5 +/- 7.7 vs. 29.1 +/- 5.9 J/m. 10(-2), Kp 0.78 +/- 0.10 vs. 0.28 +/- 0.03 mm-1, and tau 78.5 +/- 3.7 vs. 25.8 +/- 1.6 ms. After rewarming, the significant depression of LV systolic variables observed at 25 degreesC persisted: dP/dtmax 1,241 +/- 108 mmHg/s, SS% 10.2 +/- 0.8 J, SV 7.3 +/- 0.4 ml, and PRSW 52.1 +/- 3.6 m. 10(-2), whereas the diastolic values of Kp and tau returned to control. Thus hypothermia induced a significant depression of both systolic and diastolic LV variables. After rewarming, diastolic LV function was restored, in contrast to the persistently depressed LV systolic function. These observations indicate that cooling induces more long-lasting effects on the excitation-contraction coupling and the actin-myosin interaction than on sarcoplasmic reticulum Ca2+ trapping dysfunction or interstitial fluid content, making posthypothermic LV dysfunction a systolic perturbation.

Effects of highly purified eicosapentaenoic acid and docosahexaenoic acid on hemodynamics in humans.

The hemodynamic effects of highly purified eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) have not been evaluated in humans. We therefore conducted a randomized, double-blind, parallel-design intervention study to assess possible separate effects of EPA and DHA on blood pressure, heart rate, and cardiac mechanics. Healthy, nonsmoking men aged 36-56 y (n = 224) were randomly assigned to dietary supplementation with 4 g/d of ethyl ester concentrates of DHA or EPA or 4 g corn oil/d (control). Mean blood pressure at baseline was 122/77 mm Hg and was positively associated with concentrations of serum phospholipid saturated fatty acids. Blood pressure did not change during the intervention. Mean heart rate at baseline was 63.4 beats/min; it decreased 2.2 beats/min in the DHA group (P = 0.006 compared with control), increased 1.9 beats/min in the EPA group (P = 0.04 compared with control), and remained practically unchanged in the control group. In a pooled analysis, changes in heart rate were independent of baseline heart rate and were associated with changes in concentrations of serum phospholipid DHA and docosapentaenoic acid (22:5n-3). Echocardiography in a subsample of 52 men showed improved left ventricular diastolic filling in the marine oil groups compared with the corn oil group (P = 0.02). In contrast, an increase in plasma concentrations of saturated fatty acids was associated with delayed diastolic filling. We conclude that dietary DHA and EPA influence heart rate and that the fatty acid composition of plasma phospholipids may affect cardiac mechanics in humans.

[Calcium channel blockers in heart failure]. / Kalsiumkanalblokkarar ved hjartesvikt.

Patients with heart failure are particularly susceptible to the negative effects of calcium channel blockers because the failing heart demonstrates a defect in the delivery of calcium to the contractile proteins, and an attenuation of the normal sympathetic reflexes. Currently these drugs have no place in the treatment of heart failure caused by systolic dysfunction of the left ventricle. Calcium channel blockers should probably not be described for patients with coronary artery disease and left ventricular dysfunction. When the patient needs additional treatment for angina and beta-blockers or nitrates have not given satisfactory results, it may be appropriate to prescribe amlodipine or felodipine.

[Treatment of heart failure with beta-blockaders]. / Betablokkerbehandling av hjertesviktpasienter.

Since 1975 several studies have indicated that treatment with beta-adrenergic blocking drugs has a positive effect on prognosis in patients with left ventricular dysfunction. After myocardial infarction, treatment with timolol and propranolol improves prognosis in patients with symptoms of cardiomegaly and heart failure. In patients with idiopathic dilated cardiomyopathy, treatment with metoprolol improves the left ventricular ejection fraction and symptoms of heart failure, and may have a positive effect on prognosis. Recent studies of patients with chronic congestive heart failure also indicate that carvedilol has a positive effect on mortality and morbidity. The authors review some relevant studies, to stimulate the use of beta-adrenergic blocking drugs to treat certain types of heart failure.

Changes in blood flow distribution and capillary function after deep hypothermia in rat.

The present experiments were carried out in the rat to investigate the peripheral vascular function prior to the development of posthypothermic circulatory collapse. In the first study, mean arterial blood pressure, heart rate, cardiac output, regional blood flow, and plasma volume of hypothermic (4 h, 15-13 degrees C) and rewarmed rats were compared with normothermic controls. In response to hypothermia, arterial blood pressure, heart rate, and cardiac output declined markedly. After rewarming, arterial blood pressure and heart rate recovered fully, whereas cardiac output was only 33 +/- 7% of the control value (p < 0.025). Tissue blood flow was markedly depressed during hypothermia (p < 0.025), except for the abdominal skin. After rewarming, blood flow in skeletal muscle returned to within control levels, whereas blood flow in internal organs remained low (p < 0.025 vs. control). Posthypothermic plasma volume was 77 +/- 3% of control (p < 0.05). In the second study, the transcapillary colloid osmotic pressure gradient (COPp-COPi) was calculated following measurement of colloid osmotic pressure in plasma (COPp) and interstitium (COPi) in prehypothermic, hypothermic, and posthypothermic rats. The posthypothermic value of COPp-COPi was 76 +/- 4% of the prehypothermic value (p < 0.05). In conclusion this study demonstrates that the reduced cardiac output in rewarmed rats is associated with an altered regional blood flow distribution compared with that of normal rats. Capillary integrity also seemed perturbed. Thus, changes in both control and function of the peripheral vasculature are important mechanisms in the development of a posthypothermic circulatory collapse.

[Chronic left heart ventricle failure and inotropic stimulation]. / Kronisk venstre ventrikkel-svikt og inotrop stimulering.

Congestive left heart failure can be treated using three main strategies: change preload to optimize the Frank-Starling relationship, decrease after-load to reduce external work and increase cardiac contractility by inotropic stimulation. The third option is reviewed in this article, which discusses the pharmacological and clinical effects of different inotropic drugs as known in 1994. It is concluded that digitalis should be considered apart from other inotropic drugs. Even when in sinus rhythm, digitalis seems reasonable as an adjuvans to after-load reduction and diuretics. Chronic use of other inotropic drugs for congestive left heart failure is not recommended.

[Chronic heart failure. A management program. Proposal for diagnosis and treatment]. / Kronisk hjertesvikt. Handlingsprogram. Forslag til undersøkelser og behandling.

An expert meeting on the treatment of heart failure was organized by the Swedish Medical Products Agency in 1992. There were four participants from Norway. Two of these (AW, JK), in cooperation with a group of cardiologists with a special interest in heart failure, present in this article a modified Norwegian programme for treatment of chronic heart failure. When evaluating risk for patients with chronic heart failure, it is necessary to take into account both symptoms and left ventricular systolic function determined by ejection fraction. Specific recommendations are made for treatment of asymptomatic patients with left ventricular dysfunction and for symptomatic patients with mild, moderate and severe heart failure.

[Cor triatriatum with atrial fibrillation as initial symptom in adults]. / Cor triatriatum med atrieflimmer i voksen alder som første symptom.

Cor triatriatum is a rare congenital heart disease. In its classic form its consists of a fibromuscular perforated membrane which divides the left atrium and obstructs blood flow from pulmonary veins to mitral orifice. Clinical symptoms and signs resemble those of mitral stenosis. Traditionally cor triatriatum was encountered most often in infancy and childhood. We describe the case of a young man with cor triatriatum and atrial fibrillation, with syncope. He was operated on with total resection of the obstructing membrane. Modern echocardiography has made diagnosis more easy. Thus, an increasing number of cases of cor triatriatum are diagnosed in adults with few or no symptoms. Symptoms, diagnosis and treatment are discussed, with emphasis on these patients.

Absence of right ventricular isovolumic relaxation in open-chest anesthetized dogs.

During the left ventricular (LV) pump cycle, peak negative first derivative of pressure vs. time (dP/dt) occurs very close to the end of LV ejection, and there is a well-defined isovolumic relaxation period. Despite similarities between the right ventricular (RV) and LV pump cycles, recent studies indicate uncertainty as to whether peak negative RV dP/dt occurs simultaneously with RV end ejection and whether there is an isovolumic relaxation period during the RV pump cycle. To study these questions, we recorded relative timing of peak negative RV dP/dt, RV end ejection, and right atrial-RV pressure crossover in the open-chest anesthetized dog. The data demonstrate that peak negative RV dP/dt occurs an average of 60 ms before end ejection and that there is no RV isovolumic relaxation period. These findings have implications for the possible use of peak negative RV dP/dt as a marker of RV end ejection and for how time constants of pressure decay obtained during RV relaxation can be interpreted.

Selective positive end-expiratory pressure and intracardiac dimensions in dogs.

Effects of differential ventilation with general vs. selective right (R) and left (L) positive end-expiratory pressure (PEEP) on left (LV) and right ventricular (RV) end-diastolic dimensions were compared in seven pentobarbital-anesthetized dogs. All three modes of PEEP reduced LV cross-sectional area: general PEEP more than RPEEP and RPEEP more than LPEEP. General PEEP and, to a lesser degree, RPEEP decreased both the LV anteroposterior diameter and LV septum-free wall diameter, whereas LPEEP reduced the LV septum-free wall diameter only. Cardiac output was unaffected by LPEEP, whereas general PEEP (20 cmH2O) reduced cardiac output by 48%, and RPEEP (20 cmH2O) reduced it by 23%. RV septum-free wall diameter was not changed by any mode of PEEP. In conclusion, cardiac output was better maintained with selective PEEP than with general PEEP because LV filling was less impeded with selective PEEP. During LPEEP LV assumed a different configuration than during RPEEP and general PEEP, probably reflecting a different pattern of heart-lung interaction.

Effect of the pericardium on atrial systolic function.

The effect of pericardial constraint on atrial systolic function was investigated in nine acutely instrumented anesthetized dogs. Left and right atrial pressures were recorded by high-fidelity catheters; auricular diameters and free wall segment lengths were measured by sonomicrometry. Atrial function curves were constructed by relating atrial systolic dimensional shortening to atrial end-diastolic pressure during progressive volume loading. With the pericardium closed, the function curves were shifted markedly downward and rightward, such that atrial systolic shortening was reduced at any given pressure. There was a concomitant leftward and upward shift of the atrial end-diastolic pressure-dimension relationship. The relationship between atrial systolic shortening and atrial end-diastolic dimension was not shifted. These results suggest that the apparent depression of atrial systolic function with the pericardium closed is due to a restrictive effect of the pericardium on atrial filling. In conclusion, in the acutely dilated heart, the pericardium restricts atrial filling and thus causes a reduction in atrial systolic contribution to ventricular filling.

Ibuprofen abolishes the increase in leucocyte chemiluminescence observed during ischemic myocardial failure, but fails to improve hemodynamic function.

The aim of the study was to evaluate 1) whether the ability of leucocytes to produce oxygen radicals was increased by ischemia and 2) if ibuprofen pretreatment could influence leucocyte oxygen radical production, hemodynamic function, and myocardial oxygen consumption during acute ischemic myocardial failure. We studied two groups of anesthetized dogs (control and ibuprofen-treated), both subjected to coronary embolization with polystyrene microspheres (diameter 50 microns). The embolization procedure was ended when left-ventricular end-diastolic pressure in both groups exceeded 20 mm Hg. Before and after induction of ischemia leucocytes were isolated and stimulated with opsonized zymosan, and oxygen radical production was measured using the luminol-dependent chemiluminescence technique. Significant increase occurred in oxygen radical production (from 10.9 +/- 2.2 to 16.3 +/- 2.3 x 10(5) counts x 10(6) cells-1 x 60 min-1) 90 min after failure in the control group, whereas in ibuprofen-pretreated dogs oxygen radical production was unchanged. Hemodynamic registrations and myocardial oxygen consumption 90 min after failure were, however, not significantly different in control dogs and dogs pretreated with ibuprofen. Thus, in the present study, within the first 90 min of acute ischemic failure, a decrease in the ability of leucocytes to produce oxygen radicals was not related to significant changes in myocardial function.

Haemodynamic effects of selective positive end-expiratory pressure after unilateral pulmonary hydrochloric acid-aspiration in dogs.

We investigated 1) the effects of HCl-mediated acute left lung injury on regional juxtacardiac pressures and 2) the haemodynamic effects of different modes of ventilation before and after induction of left lung injury. The study was done in 7 mechanically ventilated, anaesthetized dogs. Juxtacardiac pressures and haemodynamic variables were recorded during 1) differential ventilation (DV) with zero positive end-expiratory pressure (PEEP = 0) and 2) DV with general (G) PEEP and selective right (R) and left (L) lung PEEP. Left lung injury increased left, but not right pleural pressure of pericardial pressure. Pulmonary vascular resistance (PVR) and pulmonary artery pressure (PAP) were increased moderately. Cardiac output (CO) did not change. GPEEP reduced LV filling and cardiac output markedly and by approximately the same degree before and after lung injury. The haemodynamic effects of LPEEP were minor before as well as after the induction of lung injury. RPEEP, which had only moderate haemodynamic effects during control, caused a marked reduction in cardiac function after the induction of left lung injury. The transmission of airway pressure to the pleura was reduced in the diseased lung. These results suggest that serious haemodynamic side effects may be avoided by applying PEEP selectively to the diseased lung.

Stability of myocardial O2 consumption-pressure-volume area relation in red cell-perfused rabbit heart.

We evaluated the mechanical and energetic stability of the isolated rabbit heart perfused with a suspension of bovine red cells in Krebs-Henseleit buffer in terms of the pressure-volume area (PVA) concept. PVA, the area surrounded by the end-systolic and end-diastolic pressure-volume (P-V) relations and the systolic P-V trajectory of the P-V diagram, represents the total mechanical energy generated by each cardiac contraction. Myocardial O2 consumption (VO2) per beat has been reported to be highly linearly correlated with PVA. We used the slope and VO2-axis intercept of the VO2-PVA relation as energetic parameters and the maximum P-V ratio (Emax) as a contractility index of the left ventricle (LV) and compared them every 30 min for 120 min. Emax, the slope, and VO2 intercept of the VO2-PVA relation did not change significantly over 120 min compared with their control values [7.3 +/- 2.9 mmHg.ml-1.100 g LV, (1.67 +/- 0.40) x 10(-5) ml O2.mmHg-1.ml-1, and (3.26 +/- 1.01) x 10(-2) ml O2.beat-1.100 g LV-1, respectively]. However, the goodness of the linear fit of the VO2-PVA relation decreased after 90 min (r = 0.94 control, 0.62 at 90 min, and 0.64 at 120 min). Therefore, we conclude that the isolated bovine red cell-perfused rabbit heart preparation is stable for mechanical and energetic studies for at least 60 min.