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Biomedical subjects

A Waldenström

Publications and source records attributed to A Waldenström.

At least 19 recordsLinked to original sources
PubMed2006

Pulsed tissue Doppler and strain imaging discloses early signs of infiltrative cardiac disease: a study on patients with familial amyloidotic polyneuropathy.

BACKGROUND: Familial amyloidotic polyneuropathy (FAP) is a hereditary systemic amyloidosis with cardiac involvement. As early identification of the cardiac involvement is of major clinical interest we performed this study to test the hypothesis that tissue Doppler imaging (TDI) and strain imaging (SI) might disclose cardiac involvement in patients with early stages of FAP. METHODS: Twenty-two patients with FAP and 36 healthy controls were studied. Standard M-mode and Doppler echocardiography were performed. TDI and SI were used to assess the regional longitudinal left ventricular (LV) lateral and septal and right ventricular (RV) wall functions. All time intervals were corrected for heart rate by dividing with R-R interval and presented as percentage. RESULTS: We found that patients in comparison with controls had increased LV and RV wall thickness and by using TDI a prolonged isovolumic relaxation time (IVRt) at the septal segment (15.0+/-7.0 vs 10.7+/-4.1%, p<0.05) and prolonged isovolumic contraction time (IVCt) at LV lateral (12.8+/-4.3 vs 10.1+/-3.3%, p<0.05), septal (12.5+/-3.5 vs 8.9+/-1.9%, p<0.001) and RV free wall segments (12.0+/-3.6 vs 8.3+/-2.1%, p<0.001). Strain was reduced at LV lateral basal segment (-4.6+/-14.0 vs -20.2+9.1, p<0.001), RV free wall mid segment (-16.2+/-12.8 vs -29.4+/-15.2) as well as both septal segments (-4.1+/-11.7 vs -16.2+/-9.0%, p<0.001, -8.8+/-11.5 vs -19.4+/-8.4%, p<0.001 for septal basal and mid-segment). Even in the absence of septal hypertrophy the septal strain was reduced and the regional IVCt was prolonged. CONCLUSIONS: This is the first clinical study using TDI and strain in patients with FAP showing functional abnormalities before any morphological echocardiographic abnormalities were present. Both the left and right heart functions are involved and the disease should therefore be regarded as biventricular.

Adult↗
PubMed2005

Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity.

AIMS: Patients with diabetes have an unfavourable prognosis after an acute myocardial infarction. In the first DIGAMI study, an insulin-based glucose management improved survival. In DIGAMI 2, three treatment strategies were compared: group 1, acute insulin-glucose infusion followed by insulin-based long-term glucose control; group 2, insulin-glucose infusion followed by standard glucose control; and group 3, routine metabolic management according to local practice. METHODS AND RESULTS: DIGAMI 2 recruited 1253 patients (mean age 68 years; 67% males) with type 2 diabetes and suspected acute myocardial infarction randomly assigned to groups 1 (n=474), 2 (n=473), and 3 (n=306). The primary endpoint was all-cause mortality between groups 1 and 2, and a difference was hypothesized as the primary objective. The secondary objective was to compare total mortality between groups 2 and 3, whereas morbidity differences served as tertiary objectives. The median study duration was 2.1 (interquartile range 1.03-3.00) years. At randomization, HbA1c was 7.2, 7.3, and 7.3% in groups 1, 2, and 3, respectively, whereas blood glucose was 12.8, 12.5, and 12.9 mmol/L, respectively. Blood glucose was significantly reduced after 24 h in all groups, more in groups 1 and 2 (9.1 and 9.1 mmol/L) receiving insulin-glucose infusion than in group 3 (10.0 mmol/L). Long-term glucose-lowering treatment differed between groups with multidose insulin (> or =3 doses/day) given to 15 and 13% of patients in groups 2 and 3, respectively compared with 42% in group 1 at hospital discharge. By the end of follow-up, HbA1c did not differ significantly among groups 1-3 ( approximately 6.8%). The corresponding values for fasting blood glucose were 8.0, 8.3, and 8.6 mmol/L. Hence, the target fasting blood glucose for patients in group 1 of 5-7 mmol/L was never reached. The study mortality (groups 1-3 combined) was 18.4%. Mortality between groups 1 (23.4%) and 2 (22.6%; primary endpoint) did not differ significantly (HR 1.03; 95% CI 0.79-1.34; P=0.831), nor did mortality between groups 2 (22.6%) and 3 (19.3%; secondary endpoint) (HR 1.23; CI 0.89-1.69; P=0.203). There were no significant differences in morbidity expressed as non-fatal reinfarctions and strokes among the three groups. CONCLUSION: DIGAMI 2 did not support the fact that an acutely introduced, long-term insulin treatment improves survival in type 2 diabetic patients following myocardial infarction when compared with a conventional management at similar levels of glucose control or that insulin-based treatment lowers the number of non-fatal myocardial reinfarctions and strokes. However, an epidemiological analysis confirms that the glucose level is a strong, independent predictor of long-term mortality in this patient category, underlining that glucose control seems to be an important part of their management.

Aged↗
PubMed2005

Pulmonary venous flow reversal and its relationship to atrial mechanical function in normal subjects--Umeå General Population Heart Study.

AIMS: Although pulmonary venous flow reversal (Ar) is useful in the evaluation of left ventricular (LV) diastolic function, it is often difficult to study with transthoracic echocardiography (TTE). We determined the relationship between Ar and left atrial (LA) mechanical function and sought to define surrogate measurements for Ar. METHODS AND RESULTS: A total of 130 healthy subjects, mean age 54.3+/-18.3 years, 62 women, were studied and classified into three groups: [young (Y), 25-44 years; n=44], [middle-age (M), 45-64 years; n=43] and [elderly (E), > or =65 years; n=43]. Pulmonary venous flow and LV inflow studies were performed by TTE and LV basal free-wall motion was studied by Doppler tissue imaging (DTI). All images were acquired with a superimposed electrocardiogram. RR interval was similar in all groups while LA dimension and PR interval were increased in Group E vs. Y (P<0.001). LA contraction (A(m)) on DTI, transmitral A-wave (A) and Ar were simultaneous and started 84ms after onset of P wave and this interval increased with age (P=0.02). Similarly, the time intervals from the same landmark to peak A(m), A, and Ar were prolonged with age (all, P<0.001). Despite this prolongation, peak A(m) coincided with peak Ar in every age group (r=0.97, P<0.001) and Ar acceleration and deceleration times were consistently equal. CONCLUSION: The timing of A(m) obtained by DTI can be used to accurately estimate corresponding measurements of Ar recorded by TTE in subjects without cardiac disease.

Adult↗
PubMed2005

Amyloid heart disease mimicking hypertrophic cardiomyopathy.

OBJECTIVE: To investigate the importance of transthyretin (TTR) gene mutations in explaining the phenotypic expression in patients diagnosed with hypertrophic cardiomyopathy (HCM) in northern Sweden. BACKGROUND: Hypertrophic cardiomyopathy is relatively common and often caused by mutations in sarcomeric protein genes. Mutations in the TTR gene are also common, one of which causes familial amyloid polyneuropathy (FAP), with peripheral polyneuropathy and frequently, cardiac hypertrophy. These circumstances were highlighted by the finding of an index case with amyloidosis, presenting itself as HCM. Initial rectal and fat biopsies did not show amyloid deposits. Later on, the patient was shown to carry a TTR gene mutation, and cardiac amyloidosis was confirmed by myocardial biopsy. Only then was a repeated fat biopsy positive for amyloid deposits. DESIGN: Cross-sectional study. SETTING: Cardiology tertiary referral centre. SUBJECTS: Forty-six unrelated individuals with HCM and the index case were included. Common diagnostic criteria for HCM were used. The 46 patients with HCM were previously analysed for mutations in eight sarcomeric protein genes and the TTR gene was now analysed by denaturing high-performance liquid chromatography and direct sequencing. RESULTS: One mutation in the TTR gene (Val30Met) was found in three individuals and the index case. CONCLUSIONS: Three of the 46 cases with HCM carried the Val30Met mutation, and were considered likely to have cardiac amyloidosis, like the index case. As a correct diagnosis of cardiac amyloidosis is mandatory for a potentially life-saving treatment, TTR mutation analysis should be considered in cases of HCM not explained by mutations in sarcomeric protein genes.

Adult↗
PubMed2004

Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats.

AIMS/HYPOTHESIS: The renal medullary region is particularly vulnerable to reduced oxygen concentration because of its low blood perfusion and high basal oxygen consumption. This study investigated renal metabolic changes in relation to the previously observed decreased oxygen tension in streptozotocin-induced diabetic rats. METHODS: Blood perfusion, oxygen tension and consumption, interstitial pH, and glycolytic and purine-based metabolites were determined in the renal cortex and the medulla of non-diabetic and diabetic animals by, respectively, laser Doppler flowmetry, oxygen and pH microelectrodes, and microdialysis. The importance of increased polyol pathway activity for the observed alterations was investigated by daily treatment with the aldose reductase inhibitor AL-1576 throughout the course of diabetes. RESULTS: The diabetes-induced decrease in renal oxygen tension, due to augmented oxygen consumption, did not result in manifest hypoxia in either the cortical or the medullary region, as evaluated by microdialysis measurements of purine-based metabolites. The profound alterations in medullary oxygen metabolism were, however, associated with an increased lactate : pyruvate ratio and a concomitantly decreased pH. Notably, the renal medullary changes in oxygen tension, oxygen consumption, lactate : pyruvate ratio and pH were preventable by inhibition of aldose reductase. CONCLUSIONS/INTERPRETATION: Substantial metabolic changes were observed in the renal medulla in diabetic animals. These disturbances seemed to be mediated by increased polyol pathway activity and could be prevented by inhibition of aldose reductase.

Animals↗
PubMed2003

Validity of elevated interstitial levels of taurine as a predictor of myocardial ischemic injury.

The microdialysis (MD) technique allows for continuous in vivo monitoring of dynamic changes in the interstitial levels of energy-related metabolites. The release of taurine from the myocyte has been suggested as a marker of ischemic injury. The relationship between (interstitial) taurine release and the degree of myocardial ischemic injury was evaluated following a 40 min long ischemia in a porcine heart-infarct-model. Different protocols of ischemia and reperfusion were used in order to achieve a graded level of myocardial injury. Both interstitial peak levels and the area under curve of taurine obtained during ischemia and reperfusion correlated with the degree of ischemic injury (assessed by developed infarct size estimation). The release of taurine in the myocardium measured by the MD-technique correlated with the degree of ischemic injury during ongoing ischemic insult. Hence, taurine determination in the MD-setting represents a powerful tool to follow the development of myocardial ischemic injury over time.

Animals↗
PubMed2003

Clinical outcome of coronary angioplasty in patients with ischaemic cardiomyopathy.

OBJECTIVE: To assess the clinical outcome of successful percutaneous transluminal coronary angioplasty (PTCA) in patients with poor ventricular function. METHODS: Analysis of angiographic, echocardiographic and clinical records of patients with severe LV dysfunction who underwent PTCA from January 1, 1995 to December 31, 1997 was undertaken. Forty-one patients aged 63+/-10 years, 36 men, all with significant coronary artery disease and impaired LV function (fractional shortening, FS<or=20%) were identified. Patients' data before and after angioplasty were analyzed. RESULTS: Post PTCA: angiographic success was 95.2%. Major complications occurred in 19.5% and hospital mortality was 2.7%. At 6 months after PTCA:LV fractional shortening (FS) increased from 15.9+/-3.4% to 19.6+/-6.6%, P=0.02 and consequently cardiac output from 4.28+/-0.98 to 5.34+/-1.77 l/min, P<0.01. Change in at least one class of angina and cardiac functional status was observed in 46% of patients, P<0.001, and this was maintained to the end of the year. After 12 months follow-up: restenosis occurred in 10.8%; mortality was 5.4%; event-free and actuarial survivals were 62.3% and 91.9%, respectively. CONCLUSIONS: In patients with severe LV dysfunction, continued symptomatic improvement can be achieved with successful coronary angioplasty. This is associated with significant recovery of LV systolic function and cardiac output. In order to minimize procedure-related complications, careful patient selection should be considered.

Adult↗
PubMed2003

Lipoprotein(a), Chlamydia pneumoniae, leptin and tissue plasminogen activator as risk markers for valvular aortic stenosis.

AIMS: The aim of the present study was to identify risk markers for the development of valvular aortic stenosis (AS). Lipoprotein(a) (Lp(a)) and Chlamydia pneumoniae IgG antibody titres in plasma and in circulating immune complexes as well as leptin and tissue plasminogen activator (t-PA) in plasma were studied. METHODS AND RESULTS: One hundred and one patients (41 women and 60 men, mean age 71+/-8 years) with significant AS and 101 age- and sex-matched controls were included in this study. All patients underwent aortic valve replacement at the University Hospital in Umeå, Sweden. The controls had no symptoms of cardiovascular disease and they were examined echocardiographically. An Lp(a) level >or=480 mg x l(-1), a C. pneumoniae-specific IgG titre >or=1/128, a high leptin level and a high t-PA mass concentration in plasma were identified as risk markers for AS. A strong synergism between Lp(a) and C. pneumoniae IgG antibodies in circulating immune complexes was found. CONCLUSION: Our data indicate that a chronic C. pneumoniae infection and a high plasma Lp(a) level might influence and aggravate aortic heart valve sclerosis via the formation of circulating immune complexes. The present study also strongly suggests an association between high plasma leptin, t-PA mass concentration and AS.

Aged↗
PubMed2003

Ischaemic preconditioning alters the energy metabolism and protects the ischaemic myocardium in a stepwise fashion.

AIMS AND METHODS: Recently it was suggested that ischaemic preconditioning (IP) protects the myocardium in a graded pattern as assessed by myocardial infarct size estimation. Using tissue biopsies we investigated the impact of the proposed graded pattern of protection on myocardial energy state in an open-chest porcine model of IP with either one (1xIP) or four (4xIP) episodes of preconditioning. Furthermore, we evaluated the relationship between interstitial energy-related metabolite levels obtained by the microdialysis technique and the degree of subsequent ischaemic insult. RESULTS: During the long ischaemia the difference between pre-ischaemic and post-ischaemic total adenylate pools and the sum of adenylate breakdown products (adenosine, inosine and hypoxanthine) as well as tissue lactate levels appeared as follows: non-IP > 1xIP > 4xIP (P < 0.05). Moreover interstitial peak levels of lactate, hypoxanthine and taurine displayed a graded pattern analogous to the development of ischaemic damage, where non-IP > 1xIP > 4xIP. CONCLUSIONS: We present for the first time concordant energy metabolic and morphometric data in support of IP being a stepwise phenomenon for protection of the ischaemic myocardium. Furthermore, IP resulted in proportionally higher levels of hypoxanthine (relative to inosine) in the ischaemic myocardium, suggesting a different handling of adenine nucleotide breakdown products in the IP myocardium.

Adenosine Diphosphate↗
PubMed2003

Validity of the microdialysis technique for experimental in vivo studies of myocardial energy metabolism.

OBJECTIVES: The validity of the microdialysis technique for experimental in vivo studies of myocardial energy metabolism is not known. To address this question interstitial levels of energy-related metabolites (lactate, adenosine, inosine and hypoxanthine) obtained by the microdialysis technique were compared with corresponding metabolites from myocardial biopsies at given intervals in a porcine heart model using different protocols of ischaemia and reperfusion. METHODS: In an open chest porcine heart model, interstitial levels of energy-related metabolites were monitored using the microdialysis technique. All animals (n = 23) were subjected to 120-min pretreatment followed by 40 min of regional ischaemia and 120 min of reperfusion. Tissue biopsies were obtained in the beginning, middle and at the end of the 40-min ischaemic period and at the end of the reperfusion period. Pretreatment consisted of either rest (group 1, n = 7), or rest for 90 min and one ischaemia/reperfusion (10 + 20 min) cycle (group 2, n = 9), or four ischaemia/reperfusion cycles (10 + 20 min each) (group 3, n = 7). RESULTS: Interstitial levels of energy-related metabolites monitored by the microdialysis technique correlated with tissue biopsy levels of lactate (r = 0.90, P < 0.001), adenosine (r = 0.89, P < 0.001), inosine (r = 0.88, P < 0.001) and hypoxanthine (r = 0.91, P < 0.001), respectively, which were obtained by tissue biopsies at given time intervals. These significant correlations were valid regardless of the functional state of the myocardium. CONCLUSION: We observed significant correlations between microdialysis probe levels and tissue biopsy levels of energy-related metabolites in both ischaemic and non-ischaemic tissue. These data assess the validity of the microdialysis technique (in the current setting) for studying dynamic changes of myocardial energy metabolism.

Adenosine↗
PubMed2003

Oestrogen receptor alpha gene polymorphism is related to aortic valve sclerosis in postmenopausal women.

OBJECTIVES: Aortic valvular sclerosis (AS) is an inflammatory process and not a result of normal ageing. The sclerotic process is accelerated by risk factors such as smoking and high cholesterol levels. The genetic factors for the development of AS are however unknown. Therefore the purpose of the present study was to investigate whether polymorphisms in the oestrogen receptor alpha (ORalpha) gene and in the transforming growth factor beta (TGF-beta1) gene were related to the presence of AS in postmenopausal women. DESIGN: Case-control study. SUBJECTS AND METHODS: Relationships were tested between polymorphisms in the ORalpha gene defined by the restriction enzymes PvuII and XbaI, and in the TGF-beta1 gene defined by AocI, and AS, lipid levels, and lipoprotein(a) [Lp(a)] in 41 postmenopausal female patients and 41 age- and sex-matched controls. These polymorphisms were also tested in relation to lipid levels and Lp(a), in 99 healthy Caucasian girls, aged 16.9 +/- 1.2 years. RESULTS: In the postmenopausal patients and age-matched controls, the PvuII polymorphism was independently associated with an increased risk of AS [odds ratio (OR) = 3.38; 95% confidence interval (CI) 1.13-10.09). A genotype defined by at least one restriction site in the PvuII polymorphism and two restriction sites in the TGF-beta1 polymorphism was related to a highly significantly increased risk of AS (OR = 4.58; 95% CI 1.68-12.51). In the adolescent female cohort, presence of two restriction sites in the PvuII polymorphism was associated with higher levels of total cholesterol (TC) (P = 0.02), and low-density lipoprotein cholesterol (LDL) (P = 0.04). CONCLUSIONS: We have demonstrated that the PvuII polymorphism in the ORalpha gene is related to both the presence of AS in postmenopausal women and to lipid levels in adolescent females, suggesting that this polymorphism may influence the risk of AS partly by affecting lipid levels.

Adolescent↗
PubMed2003

Imbalance of plasma membrane ion leak and pump relationship as a new aetiological basis of certain disease states.

The basis for life is the ability of the cell to maintain ion gradients across biological membranes. Such gradients are created by specific membrane-bound ion pumps [adenosine triphosphatases (ATPases)]. According to physicochemical rules passive forces equilibrate (dissipate) ion gradients. The cholesterol/phospholipid ratio of the membrane and the degree of saturation of phospholipid fatty acids are important factors for membrane molecular order and herewith a determinant of the degree of non-specific membrane leakiness. Other operative principles, i.e. specific ion channels can be opened and closed according to mechanisms that are specific to the cell. Certain compounds called ionophores can be integrated in the plasma membrane and permit specific inorganic ions to pass. Irrespective of which mechanism ions leak across the plasma membrane the homeostasis may be kept by increasing ion pumping (ATPase activity) in an attempt to restore the physiological ion gradient. The energy source for this work seems to be glycolytically derived ATP formation. Thus an increase in ion pumping is reflected by increased ATP hydrolysis and rate of glycolysis. This can be measured as an accumulation of breakdown products of ATP and end-products of anaerobic glycolysis (lactate). In certain disease entities, the balance between ATP formation and ion pumping may be disordered resulting in a decrease in inter alia (i.a.) cellular energy charge, and an increase in lactate formation and catabolites of adenylates. Cardiac syndrome X is proposed to be due to an excessive leakage of potassium ions, leading to electrocardiographic (ECG) changes, abnormal Tl-scintigraphy of the heart and anginal pain (induced by adenosine). Cocksackie B3 infections, a common agent in myocarditis might also induce an ionophore-like effect. Moreover, Alzheimer's disease is characterized by the formation of extracellular amyloid deposits in the brain of patients. Perturbation of cellular membranes by the amyloid peptide during the development of Alzheimer's disease is one of several mechanisms proposed to account for the toxicity of this peptide on neuronal membranes. We have studied the effects of the peptide and fragments thereof on 45Ca2+-uptake in human erythrocytes and the energetic consequences. Treatment of erythrocytes with the beta 1-40 peptide, results in qualitatively similar nucleotide pattern and decrease of energy charge as the treatment with Ca2+-ionophore A23187. Finally, in recent studies we have revealed and published in this journal that a rare condition, Tarui's disease or glycogenosis type VII, primarily associated with a defect M-subunit of phosphofructokinase, demonstrates as a cophenomenon an increased leak of Ca2+ into erythrocytes.

Alzheimer Disease↗
PubMed2002

Tissue Doppler analysis of age-dependency in diastolic ventricular behaviour and filling: a cross-sectional study of healthy hearts (the Umeå General Population Heart Study).

BACKGROUND: Much in the diagnosis of diastolic ventricular dysfunction is dependent upon the filling pattern, and most patients diagnosed with diastolic heart failure are elderly. Data from healthy asymptomatic individuals across a range of ages are rare. We sought to find an age-related variation in normal diastolic physiology, specifically the filling pattern and segmental myocardial longitudinal velocities. METHODS AND RESULTS: To assess the effect of normal ageing on left ventricular longitudinal function, we studied myocardial shortening and lengthening velocities using the tissue Doppler technique in 60 healthy subjects who were randomly selected from the Umeå (Sweden) General Population Register, which represents a wide range of ages (23-88 years). Myocardial velocities were documented at four left ventricular sites (anterior, left, posterior and septal) and at three levels (basal, mid-cavity and apical). Transmitral, transtricuspid and pulmonary venous flow velocities were recorded using pulsed-wave Doppler. While systolic myocardial velocities were conserved across ages, there was a marked decrease in early diastolic velocities with age (from 16 cm. s(-1)at 30 years to 9 cm. s(-1)at 80 years at the basal segment) and a corresponding significant increase in late diastolic velocities (from 10 to 16 cm. s(-1)). Although these findings were most marked at the basal level, they were also clearly manifested at the apical level. Myocardial lengthening velocities were related to transmitral flow velocities, showing a correlation of 0.64 (P<0.0001) in early diastole and 0.68 (P<0.0001) in late diastole. Finally, diastolic pulmonary venous flow velocity was found to correlate with early diastolic myocardial velocities (at the basal level, r=0.53, P<0.0001). CONCLUSIONS: Normal ageing causes a decrease in early diastolic and a substantial increase in late diastolic myocardial lengthening velocities. These changes explain the known trends in the transmitral flow pattern with age. In contrast, systolic myocardial velocities do not change significantly with age. These findings should be considered when evaluating diastolic function, especially in the elderly.

Adult↗
PubMed2001

Markedly reduced chronic nociceptive response in mice lacking the PAC1 receptor.

The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) has been proposed to have a role in nociception. Here we have used the formalin test, thermal laser stimulation and mechanical von Frey stimulation to investigate possible alteration of PAC1-/- mice nociceptive behaviour. Our finding, that PAC1-/- mice have a substantial, 75% decrease in nociceptive response during the late phase, provides clear evidence that the specific PACAP-receptor PAC1 is involved in the mediation of nociceptive responses during chronic conditions such as inflammation. PAC1-/- mice had small or no changes in the response to mechanical and thermal laser stimulation. This suggests a limited, if any, involvement of PAC1 in nociception after short-lasting stimuli. Injury-induced changes in DRG neuropeptide expression were more pronounced in PAC1-/- mice, implying neuroregulatory functions of PAC1.

Animals↗
PubMed2001

Nucleoside transport inhibition in ischemic myocardium results in enhanced taurine efflux.

We measured with the microdialysis technique energy-related metabolites in ischemic myocardium over time in an experimental pig model. Emphasis was put on the dipyridamole effect when administered in the microdialysis probe inserted in ischemic myocardium. Not only adenosine but also taurine and pyruvate concentrations were significantly higher in the microdialysate during the periods of ischemia and extracorporeal circulation with cardioplegia. The enhanced efflux of taurine in ischemic myocardium induced by dipyridamole is a new finding. A mechanistic role of taurine in the prevention of Ca(2+) overload in ischemic myocytes is discussed. Also, taurine may have stimulatory effects on glycolysis in ischemic heart.

Adenosine↗
PubMed2001

Energy-related metabolites during and after induced myocardial infarction with special emphasis on the reperfusion injury after extracorporeal circulation.

In the clinical setting great efforts have been made with contradictory results to operate upon acutely myocardial ischaemic patients. The reasons for the absence of clear-cut results are not well understood nor are they scientifically explored. To resolve this problem further, we attempted to design an experimental in vivo model to mimic acute myocardial ischaemia followed by extracorporeal circulation (ECC) and reperfusion. One of the main targets of our protocol was monitoring of myocardial energy metabolism by microdialysis (MCD) during the periods of coronary occlusion (60 min), hypothermic (30 degrees C) ECC and cardioplegia (45 min), followed by reperfusion with (30 min) and without (60 min) ECC. In eight anaesthetized, open-chest pigs, myocardial lactate, pyruvate, adenosine, taurine, inosine, hypoxanthine and guanosine were sampled with MCD in both ischaemic and non-ischaemic areas. Myocardial area at risk and infarct size were quantified with the modified topographical evaluation methods. The principal finding with this experimental setup was a biphasic release pattern of lactate, adenosine, taurine, inosine, hypoxanthine and guanosine from ischaemic myocardium. Lactate levels were equally high in reperfused ischaemic and non-ischaemic myocardial tissue. Pyruvate demonstrated consistently higher values in non-ischaemic myocardium throughout the experiment. A pattern was discernible, lactate being a marker of compromised cell energy metabolism, and taurine being a marker of disturbed cell integrity. Of special interest was the increased level of pyruvate in microdialysates of non-ischaemic myocardium as compared with its ischaemic counterpart. In conclusion, we found disturbances in energy metabolism and cell integrity not only in ischaemic but also in non-ischaemic tissue during reperfusion implying that non-ischaemic myocardium demonstrated an unexpected accumulation of lactate and pyruvate. These new findings could at least partly be explicatory to the increased risk of heart surgery in connection with acute myocardial infarction.

Adenosine↗
PubMed2001

Pre-conditioning activates adenosine utilization in a cost-effective way during myocardial ischaemia.

During pre-conditioning the interstitial concentration of adenosine, in contrast to lactate, presents a die-away curve-pattern for every successive episode of ischaemia. This die-away pattern might not necessarily be attributed to diminished adenosine production. The present study was undertaken to investigate whether pre-conditioning alters the metabolic turnover of adenosine as observed by the lactate production during ischaemia. Interstitial levels of metabolites in pre-conditioned (n=21) and non-preconditioned (n=21) porcine hearts were monitored with microdialysis probes inserted in both ischaemic and non-ischaemic tissue in an open chest heart model. Three subgroups perturbated with either plain microdialysis buffer (control), buffer containing adenosine (375 microM), or buffer containing deoxyadenosine (375 microM) were studied. All animals were subjected to 90 min of equilibrium microdialysis before 40 min of regional myocardial ischaemia and 120 min of reperfusion. Pre-conditioning consisted of four repetitive episodes of 10 min of ischaemia and 20 min of reperfusion. Significantly higher levels of inosine and lactate were found in the ischaemic tissue of the pre-conditioned subgroup receiving adenosine (P < 0.05) compared with the other two subgroups receiving deoxyadenosine and plain buffer, respectively. This difference was only valid for pre-conditioned ischaemic myocardium, and hence equal amounts of inosine and lactate were produced in the non-preconditioned ischaemic myocardium regardless of the presence of adenosine or deoxyadenosine. In the non-ischaemic myocardium baseline levels of metabolites were measured in all subgroups. Pre-conditioning favoured degradation of exogenous adenosine to inosine successively ending up in enhanced lactate production. This was probably because of the involvement of the hexose monophosphate pathway in the pre-conditioned ischaemic myocardium. This route may therefore be supplementary in energy metabolism as a metabolic flow can be started by adenosine ending up in lactate without initial adenosine 5'-triphosphate (ATP) investment. Utilization of adenosine in this way may also explain the successive die-away pattern of adenosine seen in consecutive pre-conditioning cycles.

Adenosine↗