The additive contribution from inflammatory genetic markers on the severity of cardiovascular disease.

Inflammation plays a key role in the development of atherosclerosis. Genetic differences in molecules related to inflammation have therefore been linked to the susceptibility for and severity of atherosclerosis. We hypothesized that the additive contribution from different genes of importance for inflammation would enhance the severity of cardiovascular disease. Blood samples were collected from 230 adults admitted for elective coronary angiography. A total of 130 patients had significant (>50%) stenosis in at least one main coronary artery branch and 100 had not. Six polymorphisms in five different genes were analysed: myeloperoxidase (MPO) -129G/A and -463G/A, toll-like receptor 4 (TLR4) Asp299Gly, interleukin-6 (IL6) -174G/C, surfactant protein D (SFTPD) Met11Thr and regulated upon normal T-cell expressed and secreted (CCL5) -403G/A. The IL6 polymorphism was significantly associated (P = 0.017) to angiographic significant coronary artery disease, and this relation remained after adjustment for age, gender, smoking and hypercholesterolaemia (P = 0.007). The TLR4 (P = 0.050) and SFTPD (P = 0.058) polymorphisms were also associated with the presence of coronary stenosis in univariate but not in multivariate analyses. For MPO and CCL5 no associations were found. There was a significant linear association between the number of high-risk gene variants (IL6-174CC, SFTPD 11CC and TLR4 299AA) and the proportion of patients with coronary artery disease (P < 0.0005). Inherited factors related to inflammation may increase susceptibility for severe coronary artery disease. Furthermore, the additive contribution from different inflammatory genetic markers strongly enhances the individual severity of cardiovascular disease.

Protection by superoxide dismutase and catalase in the isolated rat heart reperfused after prolonged cardioplegia: a combined study of metabolic, functional, and morphometric ultrastructural variables.

To determine the protective effect during ischaemia and reperfusion of removing oxygen radicals two groups of isolated Langendorff perfused rat hearts were arrested with cardioplegic solution at 4 degrees C and kept ischaemic at 15 degrees C for 210 min before being reperfused for 60 min at 37 degrees C. To remove oxygen radicals superoxide dismutase and catalase were added to the cardioplegic solution and to the buffer during the first 30 min of reperfusion in one group, the other group serving as control. At the end of reperfusion the first derivative of left ventricular developed pressure (dP/dt), coronary flow, high energy phosphate concentrations, and ultrastructure were determined. The ultrastructure was examined using a stereological method based on point counting and the results presented as volume fractions (Vv). DP/dt after 60 min of reperfusion was 61.6(5.6)% (mean (SEM)) of the initial values in the control group and 77.6(3.4)% in the superoxide dismutase and catalase supplemented group (p less than 0.05). In the supplemented group coronary flow was significantly higher than in the control group but only in the first part of reperfusion. The concentrations of adenosine triphosphate and creatine phosphate in the control group were 9.9(1.0) and 19.6(1.8) mumol.g-1 dry weight respectively; corresponding values in the supplemented group were 14.4(2.1) and 29.4(3.6) mumol.g-1 dry weight. The morphometric examination of the ultrastructure showed no significant difference in interstitial fluid accumulation evaluated by Vv(myocyte/myocardium) measurements and there was no difference in mitochondrial alteration between the two groups. There was, however, a significant reduction in the volume of cellular oedema (Vv(cell oedema/myocyte)) in the supplemented group.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of cod liver oil and corn oil on platelets and vessel wall in man.

Ten healthy male subjects on an ordinary diet were given daily dietary supplement of 25 ml cod liver oil (CLO) or corn oil (CO) for periods of 6 weeks in a crossover study. Significant changes were observed in the plasma total fatty acid composition. The main platelet phospholipids fractions were also significantly altered, particularly by CLO with an increase of the eicosapentaenoic acid (EPA): arachidonic acid (AA) ratio. Both supplements reduced collagen induced platelet aggregation and TXB2 production, with CLO as the most potent one. No spontaneous release of an antiaggregatory substance or 6-keto-PGF1 alpha from vein tissues were found, and the total urinary excretion of prostaglandin metabolites (E and F series) remained unchanged.

Thrombotic disc impediment in a Medtronic-Hall aortic valve prosthesis diagnosed by Doppler echocardiography followed by successful reoperation.

A case with impeded disc movement caused by thrombus formation in a Medtronic-Hall aortic valve prosthesis is reported. A correct diagnosis, including both mechanism and severity of the prosthesis failure, was established by Doppler echocardiography. The patient was promptly referred for surgery without invasive or other supplementary investigations.

Myocardial and microvascular injury following coronary surgery and its attenuation by mode of reperfusion.

In 14 patients undergoing coronary surgery, repeated atrial biopsies were obtained before and at the end of ischemia, and at 20 and 60 min of reperfusion. In half of the patients reperfusion was initiated with an abrupt rise in blood temperature and pressure, in the other half with a gradual rise. The biopsies were prepared for transmission electron microscopy and analyzed by stereological technique. In all biopsies, myocytic injury, as revealed by mitochondrial changes and intracellular edema, occurred following ischemia (P = 0.0003 and 0.007, respectively). The intracellular edema regressed following 20 min of reperfusion (P = 0.008). The myocytic mitochondrial changes persisted during reperfusion towards the end of the observation period (P = 0.0001). Interstitial edema increased following ischemia (P = 0.007) and persisted following 60 min of reperfusion (P = 0.009). The capillary part was significantly reduced after 20 min of reperfusion (P = 0.003), probably reflecting interstitial edema. Most changes were reversible in nature, although foci of irreversible changes were shown. In patients with a gradual start of reperfusion there was a significant regression of interstitial edema (P = 0.005) at 60 min reperfusion compared to the patients with an abrupt start, where the same changes seemed to persist or even increase. The study demonstrates that "reperfusion injury" occurs in human myocardium. It can be discerned from "ischemic" injury, and it may be reduced by a gentle mode of reperfusion.

Amelioration of reperfusion injury following hypothermic, ischemic cardioplegia in isolated, infarcted rat hearts.

The left coronary artery was ligated and myocardial infarction developed in 28 rats. Three weeks later, the hearts were excised and mounted in an apparatus for perfusion of non-working isolated hearts (Langendorff). Hypothermic (15 degrees C), ischemic cardioplegia was induced for either 2 or 3 1/2 h followed by reperfusion for 45 min. Half of the hearts were reperfused with an initially gradual rise in temperature and pressure of the perfusion fluid, whereas the other half was reperfused directly with the perfusate at 37 degrees C and 100 cm H2O pressure. The hearts were examined by transmission electron microscopy and randomized for stereological analysis based on point counting on electron micrographs. Cardioplegia of 2 h duration was tolerated better than cardioplegia for 3 1/2 h (interstitial edema; P = 0.03, fraction of altered mitochondria; P = 0.001). Particularly in the hearts undergoing the longest cardioplegia, myocardial injury was less severe following a gentle reperfusion as compared with those exposed to the clinically common abrupt technique (fraction of mitochondria in the myocyte; P = 0.03, fraction of altered mitochondria; P = 0.008). In the interstitium, the luminal area of capillaries was significantly increased and the endothelial swelling less pronounced in the groups undergoing the gentle reperfusion technique, (luminal/endothelial fraction; P = 0.01). The study shows that previously infarcted hearts are susceptible to ischemic damage even after 2 h of regular hypothermic, ischemic cardioplegia and that a gentle reperfusion technique significantly ameliorates reperfusion injury.

Improved energy preservation following gentle reperfusion after hypothermic, ischemic cardioplegia in infarcted rat hearts.

The influence of temperature and pressure during early reperfusion after 2 h of hypothermic, cardioplegic ischemia was investigated. Adenosine triphosphate (ATP) and creatine-phosphate (CP) were measured after 45-min reperfusion. The experiments were carried out in normal and previously infarcted rat hearts (the left coronary artery having been ligated 3 weeks earlier). Four groups, each containing six hearts, were studied. Group 1 consisted of normal hearts reperfused with an abrupt rise in temperature and pressure, group 2 of normal hearts exposed to slowly rising temperature and pressure, and group 3 and 4 of previously infarcted hearts. Reperfusion procedures in groups 3 and 4 were the same as in group 1 and 2, respectively. The study showed that previously infarcted hearts have a lowered tolerance to ischemia and that the reperfusion technique may influence the preservation of myocardial energetics, although this influence was not statistically significant in normal hearts following only 2 h of ischemia. The gently reperfused infarcted hearts had energy stores equal to the normal hearts after 2 h of ischemia and 45 min of reperfusion, whereas the infarcted hearts reperfused in a rougher mode had significantly lowered values (P less than 0.05 for ATP and P less than 0.01 for CP).

Muscle characteristics in effort angina before and after CABG.

Seven males with effort angina undertook graded ergometer tests and had muscle biopsies taken from their vastus lateralis muscle before, and three and six months after coronary bypass surgery. Muscle fibre composition (percentage of slow twitch fibres), ubiquinone (vitamin Q), and oxidative and fermentative enzyme activities were determined. After six months, muscle ubiquinone and oxidative enzymes were still depressed, indicating sustained muscle trauma. The only peripheral changes were that muscle lactate dehydrogenase and its skeletal muscle-specific subunits and isozymes were increased 35% to 40% (P < 0.001) three to six months postsurgery. Onset of blood lactate accumulation (2.0 mmol/L), symptom-limited ('maximal') exercise and peak blood lactate increased linearly over time (r = 0.52, P < 0.05; r = 0.63, P < 0.01; and r = 0.76, P < 0.001, respectively). It is suggested that the initial physical performance increase was due to improved circulatory capacity, oxygen delivery and lactate efflux, whereas the increased fermentative capacity ('anaerobic power') first contributed after a lag of three or more months. Whether the muscle histochemical changes reflected a healing process (recovery) is speculative.

Effects of initial reperfusion temperature and pressure after prolonged cardioplegic ischemic arrest. A metabolic and functional study in rat hearts.

The effects of temperature and pressure during early cardiac reperfusion after 3.5 hours of hypothermic, cardioplegic ischemia were investigated in isolated Langendorff-perfused rat hearts. The hearts were randomized in two groups and subjected to different techniques of reperfusion. The group I hearts were exposed to rapidly rising perfusion pressure and temperature, and in group II slowly rising pressure and temperature were employed. After 60 min of reperfusion, left ventricular developed pressure, coronary flow and tissue content of high-energy phosphates were evaluated. Left ventricular pressure and coronary flow were significantly better preserved in group II. Recovery of adenosine triphosphate and creatine phosphate was significantly lower in group I (5.27 +/- 0.38 and 8.72 +/- 0.62 mumol x g dry weight-1) than in group II (9.31 +/- 0.41 and 14.97 +/- 0.62). The study thus demonstrated that functional recovery, restoration of coronary flow and normalization of high-energy phosphate stores after long periods of hypothermic cardioplegic ischemia can be considerably influenced by the employed reperfusion technique.

Effect of coronary bypass surgery on anaerobic myocardial lactate metabolism during pacing-induced angina pectoris.

Myocardial lactate metabolism was studied by coronary sinus catheterization in nine patients before and 8-12 months after coronary bypass surgery. Measurements were performed at rest and during atrial pacing increased to a heart rate which produced strong chest pain. The estimation of myocardial lactate extraction and release was facilitated by a constant rate infusion of 14C lactate and coronary sinus blood flow (CSBF) was measured by thermodilution. Pre-operatively strong chest pain could be elicited in all patients and isotope data indicated a significant myocardial lactate release in all of them, although the net a-cs difference was negative in only half of them. After bypass surgery the maximum tolerable heart rate was increased by 23 beats min-1 and chest pain both at heart rate 110 beats min-1 and at the highest heart rate achieved was reduced or absent in eight of the nine patients. The increase in chest pain during pacing was quantitatively related to the increase in myocardial lactate release, and the correlation between these two variables followed the same course after the operation as it did before. It is concluded that the improvement in chest pain limited cardiac performance after bypass surgery is well correlated with the improvement in myocardial aerobic metabolism.

Muscle fibers, ubiquinone and exercise capacity in effort angina.

Seventeen male patients with ischaemic heart disease (IHD) and effort angina performed OBLA exercise stress tests (set to 2.0 mmol x l-1). They had muscle biopsies from the vastus lateralis muscle the day before coronary by-pass grafting, and from the internal and external intercostal, diaphragm and gastrocnemius muscles during surgery. They had a low WOBLA (83 +/- 6 W, mean +/- 1 S.E.M), WOBLA corresponded to 79 +/- 4% (% WOBLA) of WSL (symptom limited or 'maximal' capacity = 111 +/- 11 W). Peak blood lactate concentration averaged 2.9 mmol x l-1. Muscle fibre composition disclosed a depressed percent slow twitch (ST or 'red') muscle fibres in the vastus lateralis and intercostal muscles (%ST). The diaphragm and gastrocnemius muscles had normal %ST. Intercostal muscles had elevated values for the fast twitch muscle fibre (FT) subgroup FTa indicative of endurance adaptation. The vastus lateralis, gastrocnemius and diaphragm muscles had normal muscle ubiquinone (UQ) contents, whereas the intercostals were depleted. Plasma contents of the antioxidants UQ and alpha-tocopherol were low as compared to healthy man.

The effect of lidocaine on myocardial ischemia with asanguinous reperfusion. An in vitro study.

The effect of lidocaine on the ischemic nor-mothermic rat heart was studied in a Langendorff preparation. Ventricular fibrillation, total retrograde coronary flow and effluent lactate concentration were monitored in preischemia (control), ischemia (20 min) and reperfusion (20 min). Myocardial metabolites were determined in specimens excised at termination of reperfusion. Six hearts were infused with lidocaine in Ringer solution at onset of ischemia (group A) and six with only Ringer solution (group B). Sinus rhythm proceeded directly to diastolic arrest after 17 sec in group A, while all group B hearts showed ventricular fibrillation before arrest at 174 sec. Effluent lactate concentration was reduced in group A during the first 10 min of ischemia, but not subsequently. After 10 min of reperfusion, coronary flow was reduced by 12% in group A and 20% in group B. ATP was higher and ADP, AMP and IMP were lower in group A than in group B after 20 min of reperfusion. Creatine phosphate showed no intergroup difference, but creatine was higher in group B. Cardiac arrest with lidocaine thus reduced lactate formation during ischemia and lessened high-energy phosphate depletion after reperfusion.

Preservation of high energy phosphates during ischaemic cardiac arrest with glucose.

The possible myocardial protection by glucose-insulin-potassium infusion prior to cardioplegic ischaemic arrest was studied in rats. One group of animals was given intravenous infusions of high concentrations of glucose during 3 days. A control group received the same amount of saline. The isolated hearts were subjected to Langendorff perfusion followed by cardioplegic arrest at 15 degrees C for a period of 2 or 3.5 hours. The hearts were then subjected to reperfusion for a period of 45 min for those sustaining 2 hours of ischaemia and 60 min for those sustaining 3.5 hours of ischaemia. In the hearts that suffered 2 hours of ischaemia there were no differences in myocardial content of high energy phosphate compounds between the pretreated and controls, and there was no evidence of creatine kinase release. In the hearts exposed to 3.5 hours ischaemia, myocardial content of high energy phosphates was significantly higher in the pretreated than in the controls. The release of creatine kinase was also less, but this difference was not significant. The study indicates that preoperative treatment with glucose-insulin-potassium may improve myocardial tolerance to ischaemia.

Effect of dipyridamole (Persantin) on blood flow and patency of aortocoronary vein bypass grafts.

The effect of dipyridamole was investigated in 360 patients undergoing coronary bypass surgery. They were randomly allocated to receive dipyridamole (100 mg orally q.i.d. for 2 days preoperatively, 5 mg/kg body weight/24 h i.v. peroperatively and 100 mg orally q.i.d. for 1 year postoperatively) or placebo. Withdrawn from the study were 48 patients on dipyridamole and 57 on placebo. Cardiovascular and/or cerebrovascular events or need for anticoagulant treatment were the reasons for withdrawal in 22 (13%) of the dipyridamole, and 34 (18%) of the placebo group. Logistic regression analysis of risk factors influencing graft patency showed significant relation to peroperatively measured coronary blood flow. A positive trend of treatment was observed (p = 0.08). Vein graft blood flow measured during bypass surgery (245 patients) was significantly greater in the dipyridamole group (p less than 0.01). The occlusion rate was lower in vessels with peroperative blood flow greater than 30 ml/min (vein-marginal p less than 0.01, vein-dexter p less than 0.05, vein-diagonal 0.05 less than p less than 0.1). Dipyridamole increases coronary blood flow and graft patency following coronary bypass surgery.

Muscle ubiquinone in male effort angina patients.

Seven (7) males with effort angina and listed for coronary by-pass surgery had muscle biopsies taken from their vastus lateralis muscle for determination of muscle fiber types (%ST), ubiquinone (vitamin Q, UQ), oxidative and fermentative enzyme activities. Graded cycle ergometer exercise to determine intensities corresponding to onset of blood lactate accumulation set to 2.0 mmol x l-1 (WOBLA) and symptom limited exercise ('maximal', WSL) were also undertaken. WOBLA was positively related to %ST (r = 0.92, p < 0.001). %ST was on the other hand inversely related to UQ (r = -0.82, p < 0.05), the heart specific LD subunit LD-H (r = -0.96, p < 0.001), the isozyme LD3 as the fraction of LD (%LD3) (r = -0.93, p < 0.01), and the CK isozyme CKMB as the fraction of CK (%CKMB) (r = -0.88, p < 0.05). It was suggested that muscle UQ depletion in the patients was related to molecular oxygen and free oxygen radical formation. The lack of antioxidants then caused a radical trauma specifically to the ST fiber and their mitochondria. This could be a cause and-effect explanation for the selective ST fiber downregulation in effort angina and heart failure in general.

Effect of magnesium infusion on bleeding time in healthy male volunteers.

Intravenous magnesium has proved to be valuable in the treatment of cardiac arrhythmias and eclampsia, but the specific mode of action is not established. In this study the effect of magnesium sulphate (MgSO4) infusion on bleeding time and endogenous prostacyclin (PGI2) production in healthy male volunteers was investigated. Thirty-five males (age 18-30 years) randomized in a double-blind, placebo-controlled, cross-over study were investigated. MgSO4 was given as a bolus (8 mmol, 12 min) followed by continuous infusion (8 mmol in 108 ml saline, 120 min). Control was equal volumes of physiological saline. Heart rate, blood pressure and bleeding time (according to Ivy) were recorded as well as blood concentrations of magnesium and creatinine. Urine PGI2 was analysed as the stable metabolite 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha). Treatment with MgSO4 did not affect bleeding time (MgSO4; 8.4+/-3.5 vs. control 8.0+/-2.7 min) nor the production of PGI2 (MgSO4; 1.2 microg 6-keto-PGF1alpha/g creatinine vs. control; 1.1 microg 6-keto-PGF1alpha/g creatinine). Intravenous infusion of MgSO4 does not affect the PGI2/platelet axis in healthy male volunteers. Studies in patients with endothelium dysfunction and/or concomitant drug therapy are required before the anti-thrombogenic effect of MgSO4 in vivo is discarded.

Ultrastructural changes in rat hearts following cold cardioplegic ischemia of differing duration and differing modes of reperfusion.

Morphologic consequences of prolonged global hypothermic (15 degrees C), cardioplegic ischemia and two reperfusion techniques were studied in Langendorff-perfused rat hearts. A 'gentle' reperfusion technique, with gradual rise in perfusate temperature and pressure to physiologic levels over 30 min, was used for 12 hearts following 2-hour or 3 1/2-hour (6 in each group) ischemia. Abrupt reperfusion, with perfusate at 37 degrees C and 70 mmHg, was performed on 13 hearts (6 ischemic for 2 hours and 7 for 3 1/2 hours). Six nonischemic, perfused hearts served as controls. Randomly selected specimens from the left ventricle after 45-60 min reperfusion were prepared for transmission electron microscopy. Volume fractions of myocardial structural components were calculated from stereologic point-counting on the electron micrographs. Two-way analysis of variance revealed that interstitial edema developed with increasing ischemic time and was not influenced by reperfusion technique. The degree of endothelial damage was independent of ischemic time, but was lessened by 'gentle' reperfusion. Both mitochondrial injury and myocyte edema were less when perfusate temperature and pressure were slowly raised after 3 1/2-hour ischemia.

Ischaemic heart disease, skeletal muscle fibres and exercise capacity.

Twenty-eight male patients with ischaemic heart disease (IHD) performed OBLA (onset of blood lactate accumulation) exercise stress tests and had muscle biopsies taken from their vastus lateralis muscle the day before coronary bypass grafting. All 28 patients showed the same exercise performance pattern as compared to healthy sedentary, age-matched, controls: a low exercise intensity eliciting a blood lactate concentration of 2.0 mmol x l-1 (WOBLA), WOBLA corresponded to a high fraction (% WOBLA) of WSL (symptom limited or 'maximal' capacity), and a low peak blood lactate concentration. The high % WOBLA and low peak blood lactate indicated a reduced glycogenolytic capacity ('anaerobic' performance). Muscle fibre composition disclosed a high mean value of fast twitch (FT), type II or 'white' muscle fibres, as compared to sedentary healthy controls. This indicated that this patient group constituted an extreme subgroup of the age-matched population. The distorted muscle fibre composition in IHD could reflect both heredity as well as adaptation to physical inactivity, degenerative cytosolic properties, etc. Muscle and blood contents of a mitochondrial electron translocator and nonspecific radical scavenger, ubiquinone or coenzyme Q10(CoQ10), were low, which coincided with an elevated frequency of the fibre subgroup FT(c). The presence of the FT(c) fibre type is assumed to reflect histological trauma.

[Mitral valve plasty. A 12-year material]. / Mitralklaffeplastikk. Et 12-årsmateriale.

46 patients underwent mitral valve repair at the Regional Hospital in Trondheim/St. Elisabeth Heart Clinic, during the period 1983-95. There were 20 female patients. The valve pathology was ischemic in 40%, rheumatic in 10% and other or unknown in 50%. The surgical technique included commissurotomy (n = 9), ring annuloplasty (n = 18), resection of posterior leaflet (n = 12), Kay annuloplasty (n = 10), shortening of chordae (n = 3) and other techniques (n = 2). Postoperative complications included wound infection (n = 1), pneumonia (n = 1), mediastinitis (n = 1), pleural effusion (n = 5), renal failure (n = 1) and multi-organ failure (n = 1). One patient required re-exploration for postoperative bleeding. Three (6.5%) patients died within 30 days of surgery due to low cardiac output (n = 2) and multi-organ failure (n = 1). Nine patients (21%) died later. At follow up, within one year of surgery, marked functional improvement was registered, with only one patient in NYHA class III and none in class IV.

Heart muscle ubiquinone and plasma antioxidants following cardiac transplantation.

Nine patients who underwent heart transplantation (one female; average age 48 +/- 11, range 19-58 years) were followed in respect to contents of right-sided heart septum, blood and plasma ubiquinone (UQ), plasma alpha-tocopherol (alpha T), and plasma free cholesterol (FC). In contrast to healthy persons, substantial inter- and intraindividual variations were observed; individually low values were seen with rejection. Heart muscle UQ in well-treated patients averaged 0.33 +/- 0.08, range 0.06-0.58 micrograms mg-1 (0.38 +/- 0.09 mumol g-1 dry weight) and was not different from healthy individuals. Plasma UQ, alpha T; and FC averaged 0.63 +/- 0.33 micrograms ml-1 (P < 0.05 versus sedentary controls), 8.1 +/- 4.0 micrograms ml-1 (P < 0.01), and 0.52 +/- 0.23 mg ml-1 (P < 0.05). Corresponding molar values were 0.73 +/- 0.37 (UQ), 2.0 +/- 1.1 mumol l-1 (alpha T), and 1.42 +/- 0.54 mmol l-1 (FC). Blood and plasma UQ values were identical. A saturation like relationship was found between heart and blood UQ:blood contents below 0.7 micrograms ml-1 (0.8 mumol l-1) corresponded to markedly lowered heart contents. In four patients in whom blood samples were taken close to a fatal complication it averaged 0.42 micrograms ml-1 (0.49 mumol l-1, P < 0.01). When low heart muscle and blood ubiquinone were present, other variables such as left ventricle cardiac output or cycle ergometer performance was markedly impaired. Plasma UQ and alpha T covaried with a marker of the lipoidal deposit volume, plasma FC.(ABSTRACT TRUNCATED AT 250 WORDS)