Psychiatric and cognitive symptoms in Huntington's disease are modified by polymorphisms in catecholamine regulating enzyme genes.

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder characterized by motor, psychiatric, and cognitive manifestations. HD is caused by a CAG repeat expansion in the Huntingtin (HTT) gene but the exact pathogenesis remains unknown. Dopamine imbalance has previously been shown in HD, and furthermore dopamine is thought to be implicated in cognition, behavioral and motor disturbances. A substantiated inverse correlation between motor onset and the elongated CAG repeat in the HTT has been established. This relation does not account for the full variability of the motor onset, and efforts have been put into finding genetic modifiers of motor onset, however, mostly with unsuccessful outcome. In this study, we took an alternative approach focusing on symptom complexes and searched for modifiers of cognitive impairment and psychiatric symptoms in a well-described cohort of Danish HD gene-expansion carriers. We show that cognitive impairment and psychiatric symptoms in HD are modified by polymorphisms in the monoamine oxidase A (MAOA) and catechol-O-methyltransferase (COMT) genes and by the 4p16.3 B haplotype. These results support the theory of dopamine imbalance in HD, and point toward more personalized treatment modalities of HD in the future.

Hereditary spastic paraplegia is not associated with C9ORF72 repeat expansions in a Danish cohort.

OBJECTIVES: Hereditary spastic paraplegia (HSP) is a heterogeneous group of neurodegenerative disorders characterized by a progressive gait disorder, lower limb spasticity, hyper-reflexia, weakness and extensor plantar responses. Recently, large intronic hexanucleotide repeat expansions (GGGGCC) in C9ORF72 have been found to cause frontotemporal dementia (FTD), amyotrophic lateral sclerosis and FTD with motor neuron disease. Owing to the overlapping phenotypes among HSP, amyotrophic lateral sclerosis and FTD with motor neuron disease along with shared pathological findings, we hypothesized that C9ORF72 expansions might be a genetic risk factor or modifier of HSP. METHODS: Clinically characterized HSP patients were investigated for elongations in the hexanucleotide repeat of C9ORF72. RESULTS: Upon analyses of the repeat lengths in the C9ORF72 gene in a Danish cohort of HSP patients, we found no expansions. CONCLUSION: We conclude that HSP is most likely not associated with repeat expansions in C9ORF72.

Comparison of two sulfonylureas with high and low myocardial K(ATP) channel affinity on myocardial infarct size and metabolism in a rat model of type 2 diabetes.

AIMS/HYPOTHESIS: Sulfonylureas (SUs) may impair outcome in patients with acute coronary syndrome. Most experimental studies of the myocardial effects of SU treatment are performed in non-diabetic models. We compared the effect of two widely used SUs, glibenclamide (gb) and gliclazide (gc), with high and low myocardial K(ATP) channel affinity, respectively, at therapeutic concentrations on infarct size, left ventricular (LV) function and myocardial glycogen, lactate and alanine content before and after ischaemia/reperfusion (I/R). METHODS: Non-diabetic Wistar and diabetic Goto-Kakizaki rat hearts were investigated in a Langendorff preparation. Gb (0.1 µmol/l) and gc (1.0 µmol/l) were administrated throughout the study. Infarct size was evaluated after 120 min of reperfusion. Myocardial metabolite content was measured before and after ischaemia. RESULTS: Infarct size was smaller in diabetic hearts than in non-diabetic hearts (0.33 ± 0.03 vs 0.51 ± 0.05, p < 0.05). Gb increased infarct size (0.54 ± 0.04 vs 0.33 ± 0.03, p < 0.05) and reduced post-ischaemic LV developed pressure (60 ± 3 vs 76 ± 3 mmHg, p < 0.05) and coronary flow (4.9 ± 0.5 vs 7.1 ± 0.4 ml min(-1) g(-1), p < 0.05) in gb-treated diabetic rats compared with untreated diabetic rats. On comparing gb-treated diabetic rats with untreated diabetic rats, glycogen content was reduced before (9.1 ± 0.6 vs 13.6 ± 1.0 nmol/mg wet weight, p < 0.01) and after ischaemia (0.9 ± 0.2 vs 1.8 ± 0.2 nmol/mg wet weight, p < 0.05), and lactate (4.8 ± 0.4 vs 3.2 ± 0.3 nmol/mg wet weight, p < 0.01) and alanine (1.38 ± 0.12 vs 0.96 ± 0.09 nmol/mg wet weight, p < 0.05) contents were increased during reperfusion. Gc-treatment of diabetic and non-diabetic rats did not affect any of the measured variables. CONCLUSIONS/INTERPRETATIONS: Gb, but not gc, exacerbates I/R injury and deteriorates LV function in diabetic hearts. These effects of gb on diabetic hearts may be due to detrimental effects on myocardial carbohydrate metabolism.

Post-conditioning with cyclosporine A fails to reduce the infarct size in an in vivo porcine model.

BACKGROUND: Cyclosporine A has generated intense interest in the field of cardioprotection due to its ability to protect the mitochondria at reperfusion by blocking the opening of the mitochondrial permeability transition pore. The aim of our study was to examine the cardioprotective effect of Sandimmun, a clinically available formulation of cyclosporine A, in an in vivo large mammal model. METHODS: Forty-eight pigs were randomly allocated to one of three groups: (i) Control group (Con, n=19), (ii) Cyclosporine group, (Cyclo, n=19) Sandimmun 10 mg/kg i.v. bolus 5 min before reperfusion and (iii) Pre-conditioning group (Precon, n=10) two cycles of 10 min ischemia interspersed with 30-min reperfusion. The study was further sub-divided into a metabolic protocol, evaluating myocardial metabolism by measuring changes in the interstitial lactate concentration, and a coronary flow protocol. All animals were subjected to 40 min of left anterior descending coronary artery occlusion, followed by 180 min of reperfusion before histochemical staining and assessment of infarct size by planimetry. RESULTS: Infarct sizes were measured as: Con 51.4 +/- 16.5%, Cyclo 47.3 +/- 15.7% and Precon 2.4 +/- 3.6%, with no significant difference between the Con and Cyclo groups but a highly significant difference between the Precon and Cyclo and Con groups (P<0.0001 for both comparisons). In the Cyclo group, the interstitial lactate concentration was significantly increased compared with the Con group at 6-min reperfusion, although significantly lower at 14 min presumably due to accelerated washout. CONCLUSION: In this large animal model, a 10 mg/kg bolus administration of Sandimmun 5 min before reperfusion did not reduce the infarct size.

Cardioprotective effect of L-glutamate in obese type 2 diabetic Zucker fatty rats.

1. Because diabetic hearts have an increased threshold for cardioprotection by ischaemic preconditioning (IPC), we hypothesized that protection by L-glutamate during reperfusion is restricted in Type 2 diabetic hearts. Previously, we found that L-glutamate-mediated postischaemic cardioprotection mimics IPC. 2. Rat hearts were studied in a Langendorff preparation perfused with Krebs'-Henseleit solution and subjected to 40 min global no-flow ischaemia, followed by 120 min reperfusion. L-Glutamate (0, 15 and 30 mmol/L) was added to the perfusate during reperfusion of hearts from non-diabetic (Wistar-Kyoto) and diabetic (Zucker diabetic fatty (ZDF)) rats, studied at 16 weeks of age. The infarct size (IS)/area-at-risk (AAR) ratio was the primary end-point. Expression of L-glutamate excitatory amino acid transporter (EAAT) 1 (mitochondrial) and EAAT3 (sarcolemmal) was determined by quantitative polymerase chain reaction and immunoblotting. 3. The ISS/AAR ratio did not differ between control hearts from Wistar-Kyoto and ZDF rats (0.52 ± 0.03 and 0.51 ± 0.04, respectively; P = 0.90). L-Glutamate (15 mmol/L) significantly reduced the IS/AAR ratio in non-diabetic hearts, but not in diabetic hearts, compared with their respective controls. The higher concentration of L-glutamate (30 mmol/L) reduced infarct size in diabetic hearts to the same degree as in non-diabetic hearts (IS/AAR 0.35 ± 0.03 (P = 0.002) and 0.34 ± 0.03 (P = 0.004), respectively). The mitochondrial L-glutamate transporter EAAT1 was downregulated in hearts from ZDF rats at both the mRNA and protein levels (P < 0.0005 and P < 0.0001, respectively). However, there was no change in EAAT3 expression at the protein level. Myocardial L-glutamate content was increased by 43% in diabetic hearts (P < 0.0001). 4. Hearts from obese diabetic rats have an elevated threshold for metabolic postischaemic cardioprotection by L-glutamate. These findings may reflect underlying mechanisms of inherent resistance against additional cardioprotection in the diabetic heart.

Post-conditioning reduces infarct size in an open-chest porcine acute ischemia-reperfusion model.

BACKGROUND: Timely reperfusion is a prerequisite for myocardial salvage; however, re-oxygenation of the ischemic myocardium initiates reperfusion injury. Post-conditioning diminishes the detrimental aftermath of an acute myocardial infarction through alleviation of reperfusion injury. Ischemic post-conditioning consists of a series of brief interruptions in the coronary blood supply that has to be applied within the first minutes after re-establishing the coronary flow. METHODS: Sixteen female mixed Danish Landrace and Yorkshire pigs weighing 20 kg were included. The heart was exposed through a midline sternotomy. A snare was positioned around the left anterior descending coronary artery downstream of the second diagonal branch. After randomization to either no treatment (control group) or treatment by ischemic post-conditioning (post-conditioning group), the pigs underwent 45 min of ischemia and 180 min of reperfusion. The post-conditioning group had a post-conditioning algorithm applied consisting of 15 s of reperfusion alternating with 15 s of re-occlusion repeated 10 times. RESULTS: The groups were comparable with regard to body weight, hemodynamics and the size of the area at risk. The post-conditioning group had an absolute reduction in infarct size of 18.1% [confidence interval (CI): 6.2: 30.0%] compared with the control group (P=0.0056). In the post-conditioning group, infarction developed in 39.6+/-12.0% (1 SD) of the area at risk compared with 57.8+/-10.2% (1 SD) in the control group. CONCLUSION: When ischemic post-conditioning was applied at reperfusion, we found an absolute reduction in infarct size of 18.1% presumably attributable to a diminished reperfusion injury. The model we have developed is suitable for further studies of this promising intervention.

Health Effects of 12 Weeks of Team-Sport Training and Fitness Training in a Community Health Centre for Sedentary Men with Lifestyle Diseases.

This study compares the effects of team-sport training, for sedentary men with lifestyle diseases, with fitness training in a pragmatic set-up in a community health centre (CHC). Thirty-two men in the fitness group (FiG) and 36 men in the team-sport group (TsG) completed the training and trained for 60-90 min, two times/week for 12-16 weeks. In FiG and TsG, mean heart rate (HR) during training was 73.2% and 74.5% of HRmax, respectively. Percentage of training time above 90%HRmax was 6 ± 9% and 10 ± 15% and the percentage of participants who spent > 10% of total training time with HR > 90%HRmax was 20% and 41%, in FiG and TsG, respectively. In FiG, total fat mass was reduced by 3.5% (P < 0.01), while performance in the 6 min walking test (6MWT) increased by 11% (P < 0.001). In TsG, total fat mass was reduced by 2.2% (P < 0.01), while 6MWT performance improved by 5% (P < 0.05). Between-group differences were observed for systolic BP (P = 0.041) and mean arterial pressure (P = 0.050) in favour of TsG and for sit-to-stand test (P = 0.031) in favour of FiG. In conclusion, small-sided team sport is a worthy alternative to fitness training since the overall health effects are comparable, for example, improved balance and reduced fat mass. Team sport elicits high heart rates and improves cardiovascular health by reducing blood pressure, while fitness training improves sit-to-stand test performance related to activity of daily living.

Myocardial insulin resistance in patients with syndrome X.

Insulin resistance is common in patients with angina pectoris, a positive exercise electrocardiogram, and normal coronary angiograms (syndrome X). It is still not known whether insulin resistance affects the cardiac muscle itself and, if so, whether insulin resistance involves myocardial hemodynamics and energy metabolism. We investigated hemodynamics as well as metabolite exchanges across the heart and the forearm in eight patients with syndrome X and eight control subjects during a baseline period after an overnight fast and during a hyperinsulinemic-euglycemic clamp. Myocardial hemodynamics and metabolism were studied at rest, during pace stress, and in the recovery period after pacing. Neither coronary sinus blood flow nor forearm blood flow differed between the groups before and during the clamp. Whole body insulin-stimulated glucose uptake was decreased in the patients (15.6+/-2.1 vs. 23.1+/-2.0 micromol x kg-1 x min-1). Insulin-stimulated glucose uptake in the forearm and the cardiac muscle was equally reduced in the patients (46+/-5 and 48+/-5%). Myocardial glucose uptake correlated with total arterial delivery in the control subjects (r = 0.63, P < 0.01), but not in patients (r = 0.22, P = 0.13). Carbohydrate and lipid oxidation was similar in the two groups at rest, and changes during the clamp were not different in control subjects and patients either at rest, during pacing, or in the recovery period. Patients with syndrome X exhibit myocardial insulin resistance, but cardiac energy metabolism remains unaffected. In patients with syndrome X, insulin-stimulated glucose uptake is independent from myocardial blood flow.

A study of police operated dispatch to acute coronary syndrome cases arising from 112 emergency calls in Aarhus county, Denmark.

BACKGROUND: The accuracy of the Danish police operated "112" emergency call system was studied. Dispatch of the anaesthesiologist staffed mobile emergency care unit (MECU) to acute coronary syndrome (ACS) cases was used as an indicator of accuracy of dispatch to life threatening emergencies. METHODS: This was an observational cohort study of patients given a 112 system report of heart attack and patients with a provisional diagnosis of ACS made on scene by the MECU. Sensitivity, specificity, and positive predictive value with 95% confidence intervals (CI) were calculated. RESULTS: There were 341 reports of "heart attack" and 205 patients with ACS. Sensitivity was 75% (95% CI 68% to 80%) specificity 90% (89% to 92%) and positive predictive value 45% (40% to 50%). CONCLUSION: The accuracy of 112 dispatch of the MECU was found to be moderate. We suggest more training of dispatch staff and medical supervision.

Endothelium-dependent and -independent perfusion reserve and the effect of L-arginine on myocardial perfusion in patients with syndrome X.

BACKGROUND: Impaired vasodilatation capacity in patients with angina pectoris and a normal coronary arteriogram (syndrome X [SX]) has been reported. Most studies report on the response in epicardial vessels. This does not necessarily reflect compromised myocardial microcirculation. Lack of the NO precursor L-arginine has been suggested as a possible cause. METHODS AND RESULTS: Myocardial blood flow (MBF) was measured, using PET, at rest (MBF-rest) and during intravenous dipyridamole (MBF-DIP) in 25 women (mean age 53+/-7 years) with SX. Thirty healthy volunteers served as controls. One group (A) consisted of 15 age-matched female volunteers (54+/-10 years). The other control group consisted of 15 young healthy women (B; 24+/-5 years). In 12 SX patients, MBF-rest and MBF during cold pressor testing were also measured after infusion of L-arginine (6.7 g/min for 45 minutes). The increase in MBF after cold pressor testing was similar in the SX group compared with controls. L-arginine did not affect MBF-rest (0.83+/-0.14 versus 0.89+/-0.13 mL. g-1. min-1) or MBF after cold pressor test (0.95+/-0.10 versus 1. 03+/-0.17 mL. g-1min-1). In contrast, the hyperemic response to DIP was blunted compared with the group A controls (1.68+/-0.49 versus 2. 34+/-0.45 mL. g-1. min-1, P<0.05); this resulted in a significant reduction of the coronary flow reserve in SX patients relative to controls (2.03+/-0.53 versus 2.96+/-0.63 mL. g-1. min-1, P<0.01). CONCLUSIONS: In patients with SX, the microcirculatory response to cold, reflecting the endothelium function, is normal and unaltered by intravenous L-arginine. This suggests preserved microcirculatory endothelial function. However, a markedly attenuated hyperemic flow and flow reserve after DIP suggest a dysfunction of the adenosine-mediated endothelium-independent vasodilatation at the microcirculatory level in these patients.

Influence of nitric oxide synthase and adrenergic inhibition on adenosine-induced myocardial hyperemia.

BACKGROUND: Myocardial perfusion during adenosine-induced hyperemia is used both in clinical diagnosis of coronary heart disease and for scientific investigations of the myocardial microcirculation. The objective of this study was to clarify whether adenosine-induced hyperemia is dependent on endothelial NO production or is influenced by adrenergic mechanisms. METHODS AND RESULTS: In 12 healthy men, myocardial perfusion was measured with PET in 2 protocols performed in random order, each including 3 perfusion measurements. First, perfusion was measured at rest. Second, either saline or the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 4 mg/kg) was infused, and perfusion during adenosine-induced hyperemia was determined. Last, in both protocols, the alpha-receptor blocker phentolamine was infused, and perfusion during adenosine-induced hyperemia was determined again. Resting perfusion was similar in the 2 protocols (0.69+/-0.14 and 0.66+/-0.18 mL. min(-1). g(-1)). L-NAME increased mean arterial blood pressure by 12+/-7 mm Hg (P<0.01) and reduced heart rate by 16+/-7 bpm (P<0.01). Adenosine-induced hyperemia (1.90+/-0.33 mL. min(-1). g(-1)) was attenuated by L-NAME (1.50+/-0.55 mL. min(-1). g(-1), P<0.01). The addition of phentolamine had no effect on the adenosine-induced hyperemia (2.10+/-0.34 mL. min(-1). g(-1), P=NS). In the presence of L-NAME, however, when the adenosine response was attenuated, phentolamine was able to increase hyperemic perfusion (2.05+/-0.44 mL. min(-1). g(-1), P<0.05). CONCLUSIONS: Inhibition of endogenous NO synthesis attenuates myocardial perfusion during adenosine-induced hyperemia, indicating that coronary vasodilation by adenosine is partly endothelium dependent. alpha-Adrenergic blockade has no effect on adenosine-induced hyperemia unless NO synthesis is inhibited.

Peripheral flow response to transient arterial forearm occlusion does not reflect myocardial perfusion reserve.

BACKGROUND: Ultrasonographic evaluation of systemic arterial function is widely available, and a close relation of endothelial function in the coronary and brachial arteries has been documented. It is unknown, however, whether a similar correlation exists for their 2 microcirculatory territories and thus whether assessment of the systemic microcirculation can be used similarly as a surrogate marker of myocardial perfusion. METHODS AND RESULTS: Twenty-three patients with documented coronary artery disease (CAD; 66+/-9 years old, 18 men), 16 patients with syndrome X (SX; 56+/-5 years old, 13 women), and 45 healthy control subjects (C; 34+/-9 years old, 22 men) were studied. Myocardial perfusion was measured at rest and after dipyridamole (0.56 mg. kg(-1). min(-1) over 4 minutes) by PET, and brachial artery blood flow was measured at rest and after transient forearm ischemia by standard Doppler ultrasound techniques. Dipyridamole increased myocardial perfusion in all groups (mL. g(-1). min(-1): CAD, 0.89+/-0.27 versus 1.62+/-0.67, P:<0.001; SX, 0.82+/-0.16 versus 1.67+/-0.49, P:<0.001; and C, 0.82+/-0.15 versus 2.32+/-0.64, P:<0.001). Postocclusion forearm flow increased similarly in all groups (CAD, 52+/-18 versus 174+/-77 mL/min, P:<0.001; SX, 49+/-29 versus 202+/-82 mL/min, P:<0.001; and C, 61+/-34 versus 229+/-108 mL/min, P:<0.001). No significant correlations were found between peripheral and myocardial microcirculatory beds for either resting flow, hyperemic flow, or flow reserve in any of the groups (r(2)<0.1, P:=NS). CONCLUSIONS: The peripheral perfusion responses to transient forearm ischemia do not correlate with dipyridamole-induced myocardial hyperemia. The lack of correlation indicates different mechanisms of microvascular activation or regulation and confirms that extrapolations between findings in the 2 vascular beds are not suitable.

Cardiac metabolic and hemodynamic effects of insulin in patients with coronary artery disease.

To assess the effects of insulin in stable coronary artery disease (CAD), 2 U i.v. insulin was given to 9 control and 10 CAD patients during coronary sinus catheterization. Hemodynamic and metabolic data were obtained before and for 90 min after insulin injection. Insulin induced no changes in heart rate, mean aortic pressure, rate-pressure product, coronary sinus flow, or coronary resistance. Metabolic changes were similar in both groups and included 1) 30% decrease of arterial glucose (P less than .001) and 3-fold increase of myocardial glucose uptake (P less than .001), 2) 1.5- to 2.5-fold elevation of arterial lactate (P less than .001) and myocardial lactate usage (P less than .001), respectively, 3) 50-70% suppression of arterial levels (P less than .001) and myocardial uptake of free fatty acids (P less than .01), and 4) 10% reduction of myocardial net oxygen consumption (P less than .05). Myocardial citrate efflux increased in the CAD patients (P less than .05), whereas alanine release rose only in control patients (P less than .01), suggesting that glucose enters glycogen production in the CAD patients and pyruvate production in the control patients to a high degree. Myocardial glutamate uptake remained unchanged. In conclusion, insulin sensitivity was not altered in CAD. The insulin-induced shift from myocardial free fatty acid to carbohydrate usage may be beneficial to the ischemic heart by increasing glycogen stores, saving oxygen, and inhibiting an excess free-fatty acid concentration, which may be toxic during ischemia.

Functional significance of recruitable collaterals during temporary coronary occlusion evaluated by 99mTc-sestamibi single-photon emission computerized tomography.

OBJECTIVES: The present study evaluated the impact of recruitable collaterals on regional myocardial perfusion measured by 99mtechnetium (Tc)-sestamibi single-photon emission computerized tomography (SPECT) during temporary coronary occlusion and related these estimates to the coronary wedge pressure and electrocardiographic (ECG) ST-segment changes. BACKGROUND: Clinical variables (angina and ECG changes) and intracoronary flow and pressure recordings have indicated a protective role of recruitable collaterals on myocardial perfusion during percutaneous transluminal coronary angioplasty (PTCA). METHODS: Thirty patients (mean age 55 years, SD 9; 20 men) with stable angina pectoris and proximal nonocluding single-vessel left anterior descending coronary artery (LAD)-stenosis scheduled for PTCA were included. Visualization of recruitable collaterals by ipsilateral and contralateral contrast injection, registration of coronary wedge pressure and injection of 99mTc-sestamibi during 90-s LAD occlusions were undertaken. A rest perfusion study was performed within four days before PTCA. As an estimate of the severity of regional hypoperfusion during occlusion, an occlusion/rest count ratio was calculated (mean defect pixel count during occlusion divided by mean pixel count in identical regions at rest). RESULTS: The scintigraphic occlusion/rest count ratio was higher in patients with recruitable collaterals (n = 16), 67 +/- 11%, compared to patients without collaterals (n = 14), 60 +/- 6% (p < 0.05). The occlusion/rest count ratio correlated with the coronary wedge pressure (R2 = 0.34; p < 0.001). The occlusion/rest count ratio was lower, 61 +/- 6%, in patients with ST-segment elevation (n = 23) versus 74 +/- 9% in patients without ST-segment elevation (n = 7) (p < 0.0001). CONCLUSIONS: Using 99mTc-sestamibi SPECT imaging during brief episodes of coronary occlusion, the severity of regional myocardial hypoperfusion was reduced by the presence of recruitable collaterals in a selected patient population with proximal LAD stenoses. Our results demonstrate a protective effect of recruitable collaterals on myocardial perfusion during temporary coronary occlusion.

Regional myocardial blood flow in patients with sick sinus syndrome randomized to long-term single chamber atrial or dual chamber pacing--effect of pacing mode and rate.

OBJECTIVES: This study aimed to evaluate regional myocardial blood flow (MBF) and global left ventricular ejection fraction (LVEF) during chronic pacing in patients with sick sinus syndrome (SSS) randomized to either single chamber atrial (AAI) or dual chamber (DDD) pacing. BACKGROUND: Experimental studies indicate that chronic pacing in the right ventricular apex changes regional MBF, thereby compromising left ventricular function. METHODS: Thirty patients (age 74 +/- 10 years) were randomized to AAI (n = 15) or DDD (n = 15) pacemakers. After 22 +/- 7 months of pacing, MBF was quantified with 13N-labeled ammonia positron emission tomography scanning at 60 beats per min and 90 beats per min. Patients in the DDD group furthermore underwent MBF measurement at temporary AAI pacing, 60 beats per min. Myocardial blood flow was assessed in the anterior, lateral, inferior and septal regions, and the global mean MBF was calculated. Left ventricular ejection fraction was determined by echocardiography at pacemaker implantation and at the time of MBF measurements. RESULTS: Myocardial blood flow at rates 60 and 90 beats per min did not differ between the AAI and DDD groups. During temporary AAI pacing in the DDD group, MBF was significantly higher than during DDD pacing in both the inferior (p = 0.001) and septal (p = 0.004) regions and also globally (0.61 +/- 0.15 vs. 0.53 +/- 0.13 mL x g(-1) x min(-1), p = 0.005). In the DDD group, LVEF decreased from pacemaker implantation to time of MBF measurements (0.61 +/- 0.09 vs. 0.56 +/- 0.07, p = 0.013). Left ventricular ejection fraction during temporary AAI pacing at time of MBF measurements was not different from LVEF at pacemaker implantation. CONCLUSIONS: In patients with SSS, chronic DDD pacing reduced inferior, septal and global mean MBF as well as LVEF, as compared with temporary AAI pacing. The LVEF reversed to baseline level during temporary AAI pacing despite 22 months of permanent ventricular pacing preceding it. Augmenting pace rate to 90 beats per min increased MBF equally in the two treatment groups.

Energy stores and metabolites in chronic reversibly and irreversibly dysfunctional myocardium in humans.

OBJECTIVES: Our goal was to study metabolic energy stores and lactate content in chronic reversibly and irreversibly dysfunctional myocardium. BACKGROUND: It is unknown whether metabolism is deranged in chronic reversibly and irreversibly dysfunctional myocardium in humans. Semiquantitative histological examinations have shown altered mitochondrial morphology and glycogen accumulation in dysfunctional regions. METHODS: We studied 25 patients with a mean ejection fraction of 38 +/- 9% scheduled for coronary artery bypass surgery. Regional perfusion and metabolism were assessed by positron emission tomography, and regional function was assessed by echocardiography. Perioperative myocardial biopsies were obtained from a control region and from a dysfunctional region. We analyzed biopsies for contents of noncollagen protein (NCP), ATP, ADP, AMP, glycogen and lactate. Six months after surgery we assessed wall motion by echocardiography to group patients in those with (n = 11) and without (n = 14) functional improvement. RESULTS: Reversibly dysfunctional myocardium had reduced perfusion (0.59 +/- 0.16 vs. 0.69 +/- 0.20 ml/g/min, p < 0.05), similar glucose-tracer uptake (92 +/- 12 and 95 +/- 14%), ATP/ADP ratio (2.4 +/- 1.1 and 2.4 +/- 0.7), glycogen content (631 +/- 174 and 632 +/- 148 nmol/microg NCP) and lactate levels (59 +/- 27 and 52 +/- 29 nmol/microg NCP) compared with control regions. Irreversibly dysfunctional regions (n = 14) had severely reduced perfusion (0.48 +/- 0.15 vs. 0.72 +/- 0.12 ml/g/min, p < 0.001) and glucose-tracer uptake (52 +/- 16 vs. 94 +/- 15%, p < 0.001), reduced ATP/ADP ratio (1.5 +/- 0.9 vs. 2.3 +/- 0.9, p < 0.05), similar glycogen content (579 +/- 265 vs. 593 +/- 127 nmol/microg NCP) and increased lactate levels (114 +/- 52 vs. 89 +/- 24 nmol/microg NCP, p < 0.01) compared with control regions. CONCLUSIONS: Contents of metabolic energy stores and lactate in chronic reversibly dysfunctional myocardium were preserved. In contrast, energy stores were depleted in myocardium without functional recovery after revascularization.

Determination of high energy phosphates and glycogen in cardiac and skeletal muscle biopsies, with special reference to influence of biopsy technique and delayed freezing.

OBJECTIVE: The aim was to clarify the influence of biopsy technique and the effects of temporal delay between sampling and freezing on tissue contents of labile metabolites. METHODS: Cardiac and skeletal muscle concentrations of adenine nucleotides, phosphocreatine, creatine, and glycogen in pigs were determined in endomyocardial and transmural myocardial biopsies and in skeletal muscle biopsies obtained with either endomyocardial bioptome or Tru-cut needle. The influence of the temporal delay between biopsy sampling and freezing was evaluated by keeping the biopsies at room temperature for varying intervals up to 300 s before freezing. RESULTS: Skeletal muscle showed higher concentrations of creatine compounds and lower contents of ADP and AMP than cardiac muscle, whereas ATP, total adenine nucleotide pool, and glycogen were similar. Lower phosphocreatine contents were found both in endomyocardial biopsies and in skeletal muscle biopsies obtained with bioptome compared to transmural myocardial biopsies and skeletal muscle biopsies obtained with Tru-cut needle, respectively. Other metabolites were unaffected by the biopsy technique. With extended delays between biopsy sampling and freezing, an increase in skeletal muscle phosphocreatine averaging 26% after 5 min was observed. In the heart, a decrease in glycogen content averaging 42% after 5 min was found. These changes were not related to the biopsy procedure and were not observed within the period usually required to freeze biopsies in experimental as well as clinical settings. CONCLUSIONS: There are essential metabolic differences between cardiac and skeletal muscle. Low endomyocardial phosphocreatine levels are influenced by the biopsy technique, compromising the use of endomyocardial biopsies for establishing myocardial phosphocreatine content. Reliable measurements of adenine nucleotides and glycogen can be obtained with endomyocardial biopsies.

Comparison of non-collagen protein and total creatine as reference for determination of energy stores in endomyocardial biopsies.

OBJECTIVE: The aim was to establish a reliable reference system for biochemical measurements in endomyocardial biopsies. METHODS: Myocardial tissue samples were obtained from pigs before and after cardioplegic arrest and reperfusion. Non-collagen protein content was evaluated as a non-specific reference system and compared with total creatine content representing a specific myocardial reference system. The influence of base strength, extraction temperature, and extraction time on protein yields was determined in tissue precipitates redissolved in NaOH. Interference from protein of collagenous origin was excluded by hydroxyproline determinations. Variability of myocardial ATP content in relation to non-collagen protein and total creatine was compared in endomyocardial biopsies taken before and after cardioplegic arrest and reperfusion. RESULTS: The two methods showed comparable analytical precision. Apart from an interference in 1.0 mol.litre-1 NaOH for extended extraction periods at high temperatures, myocardial protein yields increased with increasing base strength, extraction temperature, and extraction time. During cardioplegic arrest and reperfusion heart weight increased due to oedema. Simultaneously, myocardial non-collagen protein content decreased. No change in total creatine was found during cardioplegic arrest but there was a significant loss of creatine after reperfusion. Comparison of variability in myocardial ATP content with non-collagen protein or total creatine as reference systems revealed no difference. CONCLUSIONS: Determination of non-collagen protein can be optimised with standardised conditions for protein extraction in tissue precipitates. Employment of total creatine as a reference system does not reduce variability of myocardial metabolite determinations in endomyocardial biopsies compared with non-collagen protein. Loss of myocardial creatine may in itself provide additional information about myocardial injury but this makes it unsuitable as a reference system for measuring metabolic changes during reperfusion. Multiple biopsies seem necessary for estimation of myocardial energy stores.

Decreased insulin binding to monocytes from normal pregnant women.

To ascertain whether the decrease of glucose tolerance in pregnancy might be mediated by changes in insulin receptors, we have studied insulin binding to monocytes in 12 normal women during late pregnancy and 14 healthy, young, normal weight, nonpregnant female controls. The pregnant women had significantly higher fasting insulin concentrations in plasma than the controsl (18 +/- 3.5 vs. 8 +/- 1.1 microU/ml; P less than 0.01). Fasting concentrations of glucose and ketone bodies in plasma were not significantly different in the two groups. Insulin binding to monocytes from pregnant women was about 35% lower at each insulin concentration tested compared to the nonpregnant controls (P less than 0.01 at tracer insulin concentrations). Changes in cellular insulin binding were due to changes of the receptor number per cell, whereas the receptor affinity was unaffected. Insulin binding was not significantly correlated with the fasting plasma insulin in either of the two groups (P less than 0.1). Our results suggest that the deterioration of glucose tolerance in normal late pregnancy might be explained by a decrease of insulin sensitivity caused by a reduction of the number of insulin receptors.

Measurement of myocardial glucose uptake in patients with ischemic cardiomyopathy: application of a new quantitative method using regional tracer kinetic information.

UNLABELLED: Quantification of myocardial glucose uptake (MGU) by 18F-fluoro-2-deoxyglucose (FDG) using PET may be inaccurate, because the correction factor that relates myocardial FDG uptake to MGU, the lumped constant (LC), is not a true constant. Recent studies have shown that analysis of FDG time-activity curves allows determination of individual LCs and that variable LCs yield accurate determination of MGU. We compared the magnitude of the LC in different regions of the heart in patients with ischemic cardiomyopathy. METHODS: Twenty patients with ischemic cardiomyopathy and an average ejection fraction of 33% underwent dynamic 13N-ammonia and FDG PET. We determined myocardial perfusion and MGU in 177 regions classified as control (71 regions), mismatch (50 regions) and match (56 regions), according to findings on PET and echocardiography. Regional MGU was calculated with both regional LCs and a fixed LC of 0.67. RESULTS: All results were expressed as mean +/- SD. Myocardial perfusion was highest in control regions (0.52+/-0.18 mL/g/min), reduced in mismatch regions (0.43+/-0.19 mL/g/min; P < 0.05 versus control) and severely reduced in match regions (0.28+/-0.17 mL/g/min; P < 0.001 versus control and mismatch). Regional LCs ranged from 0.45 to 1.30 and differed between patients (P < 0.001). Regional LCs were similar in regions diagnosed as control (0.78+/-0.23), mismatch (0.80+/-0.24) and match (0.72+/-0.21). MGU (micromol/g/min) calculated by regional LCs was similar in control (0.52+/-0.16) and mismatch (0.49+/-0.19) regions and decreased in match regions (0.31+/-0.12, P < 0.001). The agreement between MGU calculated with variable and fixed LCs was poor. CONCLUSION: The LC used in the calculation of MGU was not affected by regional differences in the metabolic state of the myocardium. However, the LC varied substantially between patients in control, mismatch and match regions. These findings indicate that quantitative measurements of MGU using a fixed LC must be interpreted with caution.