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Biomedical subjects

K Kjeldsen

Publications and source records attributed to K Kjeldsen.

At least 19 recordsLinked to original sources
PubMed2003

Severe intracellular magnesium and potassium depletion in patients after treatment with cisplatin.

The purpose of this study is (1) to evaluate skeletal muscle magnesium (Mg) and potassium (K) during treatment with cisplatin; (2) to evaluate the predictive value of plasma (P)-Mg for intracellular Mg during cisplatin treatment; and (3) to evaluate whether changes in intracellular K influence skeletal muscle Na,K-ATPase. In all, 65 patients had a needle muscle biopsy obtained before and 26 patients both before and after cisplatin treatment. Biopsies were analysed for Mg, K, and Na,K-ATPase concentrations, and P-Mg and P-K determined. Treatment with a total dose of approximately 500 mg (270 mg m(-2) surface area) cisplatin over 80 days was associated with reductions in muscle [Mg] (95% CI) (8.95 (8.23-9.63) to 7.76 (7.34-8.18) mumol g(-1) wet wt. (P<0.01), and muscle [K] (90.81 (83.29-98.34) to 82.87 (78.74-87.00) mumol g(-1) wet wt. (P<0.05), as well as in P-Mg 0.82 (0.80-0.85) to 0.68 (0.64-0.73) mmol l(-1) (P<0.01 but not in P-K (4.0 (3.8-4.1) vs 3.8 (3.7-4.0) mmol l(-1)). No simple correlations were observed between P-Mg and muscle [Mg], or between P-K and muscle [K], either before (n=65) or after (n=26) treatment with cisplatin. The changes in [Mg] and [K] were not associated with changes in the muscle Na,K-ATPase concentration. Following treatment with cisplatin, an approximately 15% decline in P-Mg was accompanied by an approximately 15% loss of muscle [Mg], as well as an approximately 10% reduction of muscle [K] and fatigue and muscle weakness previously ascribed to hypomagnesaemia may therefore also be well explained by muscle K depletion observed despite normal levels of P-K. There was no correlation between P-Mg and SM-Mg or between P-K and SM-K. Thus, P-Mg and P-K are not reliable indicators for Mg and K depletion during treatment with cisplatin. However, the majority of patients will present Mg and K depletion after cisplatin therapy and of these only very few patients will present a low P-Mg or P-K. Therefore, routine supplementation should be considered in all patients receiving cisplatin.

Adenosine Triphosphatases↗
PubMed2003

Diabetes- and semi-starvation-induced changes in metabolism and regulation of Na,K-ATPase in rat heart.

AIMS/HYPOTHESIS: In comparison with healthy controls, rats with streptozotocin-induced diabetes exhibit retarded gain in body weight. This is generally attributed to lowered protein synthesis resulting from abnormal metabolism. Furthermore, decreased abundance and activity of Na,K-ATPase in heart and skeletal muscle has been described. However, decreased gain in body weight per se is accompanied by a down-regulation of skeletal muscle Na,K-ATPase. Thus, the aim of the present study was to evaluate cardiac Na,K-ATPase in semi-starvation and diabetes. METHODS: Diabetes was induced in male Wistar rats with streptozotocin. In healthy parallel running control rats body weight gain was kept reduced by limited food intake. RESULTS: Semi-starved and diabetic rats demonstrated 18 and 16% (p < 0.05) retarded gain in body weight after 63 days. As compared to semi-starved rats, diabetic animals exhibited a 59-273% (p < 0.05) increase in glucose, glycohaemoglobin, triglyceride and cholesterol plasma levels. Activity of heart K-pNPPase, reflecting Na,K-ATPase, in crude membrane homogenates was reduced by 29 and 10% (p < 0.05) by diabetes and semi-starvation. The age-dependent reduction in heart K-pNPPase in normal controls was 6%. After subtracting the age-dependent change, the reductions were 25 and 4% in diabetes and semi-starvation, respectively. After subtracting the semi-starvation-associated change, the diabetes-induced reduction was 22-27%. The reduction was in accord with measurements of Na,K-ATPase activities in partially purified membranes, Na,K-ATPase isoforms and cytochemical evaluations. Expressed per heart, the reduction in Na,K-ATPase was 30%. CONCLUSIONS/INTERPRETATION: Streptozotocin-induced diabetes selectively reduces heart Na,K-ATPase concentration by around 1/4, which reduces the capacity of the heart for maintaining K- and Ca-homeostasis. This may pose a risk of arrhythmias and may be associated with heart failure in diabetic cardiomyopathy.

Animals↗
PubMed2002

Myocardial Na,K-ATPase: the molecular basis for the hemodynamic effect of digoxin therapy in congestive heart failure.

Congestive heart failure may be deemed the epidemic of cardiology in the 21st century in the industrialized part of the world. Although new therapies improving morbidity and mortality from chronic heart failure have emerged it is likely that there is a growing role for digoxin. Thus, digoxin treatment is known to control symptoms of congestive heart failure when added to standard therapy. In this setting, we review the prevailing knowledge of the Na,K-ATPase, the cellular receptor for the inotropic action of digitalis glycosides, in relation to the hemodynamic effect of digoxin. It is concluded that if improvement of hemodynamics is needed in congestive heart failure, this knowledge should be taken into account and in many cases digoxin should be added to standard therapy. Digoxin is still the only safe inotropic drug for oral use that improves hemodynamics. Digoxin should be used to heart failure patients in sinus rhythm when they after institution of mortality reducing treatment still have heart failure symptoms, and to patients intolerant to heart failure mortality reducing drugs. Digoxin should probably in heart failure patients with sinus rhythm be given in the lowest possible dose that relieves symptoms sufficiently.

Aged↗
PubMed2000

HMG CoA reductase inhibition reduces sarcolemmal Na(+)-K(+) pump density.

OBJECTIVES: HMG CoA reductase inhibitors reduce cellular availability of mevalonate, a precursor in cholesterol synthesis. Since the cholesterol content of cell membranes is an important determinant of Na(+)-K(+) pump function we speculated that treatment with HMG CoA reductase inhibitors affects Na(+)-K(+) pump activity. METHODS: We treated rabbits and rats for 2 weeks with the HMG CoA reductase inhibitor lovastatin and measured Na(+)-K(+) pump current (I(p)) in isolated rabbit cardiac myocytes using the whole cell patch-clamp technique, K-dependent p-nitrophenyl phosphatase (p-NPPase) activity in crude myocardial and skeletal muscle homogenates, and vanadate-facilitated 3H-ouabain binding in intact skeletal muscle samples from rats. RESULTS: Treatment with lovastatin caused statistically significant reductions in I(p), myocardial and skeletal muscle K-dependent p-NPPase activity and 3H-ouabain binding in the myocardium and skeletal muscle. The lovastatin-induced decrease in I(p) was eliminated by parenteral co-administration of mevalonate. However, this was not related to cardiac cholesterol content. CONCLUSIONS: Treatment with lovastatin reduces Na(+)-K(+) pump activity and abundance in rabbit and rat sarcolemma.

4-Nitrophenylphosphatase↗
PubMed2000

A novel missense mutation, Leu390Val, in the cardiac beta-myosin heavy chain associated with pronounced septal hypertrophy in two families with hypertrophic cardiomyopathy.

OBJECTIVE: An examination of the genetic background and phenotypic presentation of familial hypertrophic cardiomyopathy (FHC) with respect to specific mutations in the MYH7-gene encoding the cardiac beta-myosin heavy chain. SETTINGS: Two families (n = 22) from a cohort of 67 families with FHC were studied at the National University Hospital, Rigshospitalet, Copenhagen. METHODS: Clinical, non-invasive examinations of all included family members followed by molecular genetic analysis including PCR-single strand conformation polymorphism/heteroduplex (SSCP/HD) analysis and sequencing of exon 3-23 of the MYH7-gene. RESULTS: We found FHC associated with a missense mutation in two families, i.e. a C > G transversion at position g10124 and a G > T transversion at position g10126 causing the change of a leucine residue at codon 390 to a valine residue. The mutation is located in the actin-binding region of the beta-myosin heavy chain. The leucine residue is evolutionarily conserved in vertebrate myosins. In the two families, the phenotypic presentations in the clinically affected were characterized by asymmetric septal hypertrophy (septum diameter 18.8 (5.0) mm (mean (SD)) with only minor involvement of the left ventricular free wall (posterior wall diameter 11.0 (2.2) mm). Furthermore, the left ventricular systolic and diastolic functions were well preserved, even at a high age. The symptomatic status of the clinically affected patients depended on the presence or absence of a concomitant left ventricular outflow tract gradient. CONCLUSIONS: We report a novel missense mutation associated with FHC caused by a double nucleotide transversion. The penetrance of the mutation was not complete, but in clinically affected patients the mutation gives rise to an echocardiographic phenotype, predominantly characterized by pronounced septal hypertrophy.

Adolescent↗
PubMed2000

Outcome of septal myectomy in patients with hypertrophic obstructive cardiomyopathy.

OBJECTIVES: To study the outcome of septal myectomy in patients with hypertrophic obstructive cardiomyopathy. DESIGN: Septal myectomy in patients with hypertrophic cardiomyopathy with obstruction of the left ventricular outflow tract (HOCM) is symptomatically effective, and complication rates have been found to be low in large centres performing the procedure routinely. Representing a small centre we studied the outcome after septal myectomy in 11 consecutive patients, aged 44 +/- 21 (mean +/- SD) years with HOCM myectomized at our institution from 1991 to 1998. The patients were evaluated preoperatively using echocardiography and left-sided heart catheterization. RESULTS: Eight patients were operated on after medical treatment had failed and three after sudden deterioration of cardiac function. A Morrow myectomy was performed in 10 patients and a modified Konno procedure in one. Significant reductions were observed in left ventricular outflow tract gradients (77 +/- 29 to 10 +/- 7 mmHg, p < 0.01; n = 11), the degree of mitral valve regurgitation (grades 0-3) (1.7 +/- 1.0 to 0.8 +/- 0.7, p < 0.01; n = 11), NYHA functional classification score (2.4 +/- 1.0 to 1.5 +/- 0.7, p < 0.01; n = 11) and all five patients with angina preoperatively had an improved CCS angina classification score. There were no operative or early postoperative (30 days) deaths. One patient operated on with the modified Konno procedure was reoperated for a septal patch suture leak. During follow-up (43 +/- 24 months, range 11-83), the linearized mortality rate was 3.6% per year. One patient died from a pancreas cancer, one probably from coronary artery disease and one suddenly of unknown cause. CONCLUSION: We conclude that septal myectomy efficiently relieves symptoms in HOCM patients, possibly reflecting the direct as well as secondary effects of left ventricular outflow tract gradient reduction. The present results, obtained at a smaller centre for this procedure, should be considered when choosing from available therapeutic alternatives when medical therapy fails: dual chamber pacemaker implantation, percutaneous transluminal septal myocardial ablation or myectomy.

Adolescent↗
PubMed2000

Receptor occupancy with digoxin vs receptor occupancy with a putative endogenous digitalislike factor.

The possibility that an endogenous ligand for the digitalis receptor might exist has been a source of speculation resulting in efforts over the past decades to identify such a hormone. In the current context it is of interest that prolonged wash of myocardial and skeletal muscular samples from subjects who were not in digoxin treatment generally resulted in small tendencies to increase 3H-ouabain binding ranging from 2 to 9% and from -2 to 7%, respectively. It may be appreciated that neither wet weight nor water content of left ventricular or skeletal muscular samples have been found to change as a result of the prolonged wash. Although these tendencies most likely are a mere play of chance, it may be argued that the studies did not entirely rule out the possibility of the existence of a quantitatively small amount of endogenous digitalislike factor. However, based on the evaluations of receptor occupancy with digoxin during treatment of 24-34% in the left ventricle and 9-13% in skeletal muscle, it would seem reasonable to expect that a comparatively larger fraction of digitalis receptors should be occupied by a putative endogenous digitalislike factor, if such a factor were to be of any physiological significance.

Binding, Competitive↗
PubMed2000

Na,K-ATPase in the myocardium: molecular principles, functional and clinical aspects.

The role that Na,K-ATPase plays in Na+ and K+ antiport through the sarcolemma, in cation-homeostasis in cardiomyocytes as well as in excitation-contraction coupling and cell signalling in the myocardium is now widely recognized. It was its key importance for the cell membrane function that kept this enzyme intensively studied during the last three decades and finally brought to its discoverer the deserved Nobel Prize. Almost weekly are appearing new data concerning structure, function, regulation and role of the Na,K-ATPase in different physiological and pathological conditions. The special importance of the enzyme for heart function as well as the great amount of data that is concerned specifically with the heart Na,K-ATPase and accumulated since yet, started to call for setting them in order. The present paper updates basically important data on the cardiac Na,K-ATPase in relation to its specific properties, molecular mechanisms of function, mode of action, humoral and pharmacological modulation, adaptability, physiological role and clinical aspects.

Animals↗
PubMed1999

Familial hypertrophic cardiomyopathy associated with a novel missense mutation affecting the ATP-binding region of the cardiac beta-myosin heavy chain.

Mutations in the cardiac beta -myosin heavy chain gene (MYH7), and other genes encoding cardiac sarcomere proteins may cause familial hypertrophic cardiomyopathy (F-HCM), an autosomal dominant disease, characterized by myocardial hypertrophy. We analysed the MYH7 gene in three generations of a family with one borderline and four clinically verified cases of hypertrophic cardiomyopathy, and identified a mutation in exon 7 changing the 190 arginine residue into a threonine residue. The mutation is located in the ATP-binding region of the myosin head and alters the charge in the F-helix close to the phosphate-binding P-loop. The mutation may thus interfere with the coupling between ATP-hydrolysis and the transition into mechanical energy. In conclusion, the novel Arg190Thr mutation in exon 7 of the MYH7 gene is associated with the development of symptomatic myocardial hypertrophy in adults.

Adenosine Triphosphate↗
PubMed1998

Chronic K-supplementation decreases myocardial [Na,K-ATPase] and net K-uptake capacity in rodents.

The effects of high K intake on plasma K, myocardial K content and Na,K-ATPase concentration and on myocardial K uptake during KCl infusion were evaluated in rodents. Myocardial Na,K-ATPase was quantified in crude homogenates by K-dependent pNPPase activity in rats, and in intact samples by3H-ouabain binding in guinea pigs. Na, K-ATPase alpha isoform distribution was assessed by immunoblotting. Plasma K was monitored in anesthetized rats during intravenous infusion of 0.75 mmol KCl/100 g body weight/h. A significant increase in plasma K was observed after 2 days of K supplementation, 4.9+/-0.2 (mean+/-s.e.m.)v 3.0+/-0.2 mmol/l in weight matched controls ( P<0.01,n=5) and this difference remained stable. After 1 day, a significant myocardial K content increase was obtained, 86. 2+/-3.0v 76.7+/-1.9 micromol/g wet weight (P<0.05, n=5); after 4 days myocardial K stabilized 4.9+/-1.2 micromol/g wet weight above control level (P<0.05,n=5). From the 4th day, a significant decrease in myocardial K-dependent pNPPase activity was observed, 1.18+/-0.04v 1. 31+/-0.01 micromol/min/g wet weight in weight matched controls (P<0. 05,n=5); after 2 weeks the decrease was 29% (P<0.05,n=5), with a reduction in alpha1-isoform abundance by 24% (P<0.05,n=5), and a tendency to a decrease in alpha2 of 10% (n.s.,n=5). The measurements were validated by 3H-ouabain binding to myocardial samples from guinea pigs K-supplemented for 2 weeks, showing a decrease of 21% (P<0.05,n=5). During KCl infusion, the myocardial K content increase rate was reduced by 52% (P<0.05) in the K-supplemented rats. The observed effects of K-supplementation on plasma K, myocardial K content and myocardial K-dependent pNPPase activity were abolished within 2 days after reallocation to chow with normal K content. In conclusion, high K-intake is associated with significantly and reversible increased plasma and myocardial K content, and decreased myocardial Na,K-ATPase concentration and net myocardial K uptake capacity. Thus, the heart is protected from major increases in intracellular K concentrations during chronically-high K-intake.

4-Nitrophenylphosphatase↗