Cerebrovascular, cardiovascular and renal hypertensive disease after hypertensive disorders of pregnancy.

BACKGROUND: Strong associations have been established in nationwide registry studies between hypertensive disorders of pregnancy (HDP) and later vascular morbidities and mortality. The aim of this case-control study is to examine the interdependent relationships of different predictive factors for vascular disease and HDP, because they are not clearly elucidated due to lack of detail in registries. METHODS AND RESULTS: We assembled three different case groups of women who had cerebrovascular, cardiovascular, or hypertensive kidney disease before the age of 55. The control group consisted of age-matched women who underwent hysterectomy for benign reasons. We assessed the occurrence of HDP in previous pregnancies. The strength of the association with vascular morbidities was tested with multivariable logistic regression in comparison with classic vascular risk factors. In all case groups, previous HDP occurred more frequent than in the control group. In logistic regression analysis, previous HDP were the strongest predictor in the cerebrovascular group (OR 4.2; 95% confidence interval [CI] 1.6-11.0). In the cardiovascular group and the kidney failure group a similar association was found, however, this was not statistically significant (OR 4.4 (95% CI 0.82-4) and 2.9 (95% CI 0.61-14), respectively). CONCLUSIONS: Previous hypertensive disorders of pregnancy are a strong predictor for later vascular morbidity. This is partially mediated through the presence of classic vascular risk factors, but our data suggest it is also an independent predictor.

Development of a brief questionnaire (ICQ-S) to monitor inhaled corticosteroid side-effects in clinical practice.

BACKGROUND: Side-effect concerns impede adherence with inhaled corticosteroids (ICS) and often underlie poor asthma control. We developed a brief version (ICQ-S) of the 57-item Inhaled Corticosteroids side-effect Questionnaire (ICQ) to facilitate side-effect monitoring in busy clinics. METHODS: Part 1: After completion by 482 patients with doctor-diagnosed asthma, each ICQ item underwent item reduction analysis. Part 2: Patients prescribed ICS for asthma completed the ICQ at baseline (BL), ICQ-S at day 14 (D14) and day 28 (D28), and 6-item Asthma Control Questionnaire (ACQ) and Mini Asthma Quality of Life Questionnaire (MiniAQLQ) at BL, D14 and D28. 14-day test-retest reliability was assessed by intraclass correlation coefficient (ICC) between ICQ-S scores and internal consistency by Cronbach's alpha (α) coefficient and item-total correlations of ICQ-S. Criterion validity was assessed by correlations (Spearman's rho) between ICQ and ICQ-S total score. Patients reported duration and difficulty of ICQ-S completion at D28. RESULTS: Part 1: The ICQ-S consists of fifteen local/systemic ICS side-effects of similar range to the full ICQ. Part 2: 62 asthma patients (mean ACQ score 0.79 ± SD 0.83) prescribed daily ICS [BDP-equivalent median dose 1000 µg (IQR: 500, 1000)] participated. ICC between ICQ-S scores was 0.90. All item-total correlations were rho ≥ 0.20. The ICQ-S demonstrated criterion validity, for example, ICQ and ICQ-S were strongly associated (rho = 0.86). 81% of patients completed the ICQ-S within 5 minutes and 97% found completion 'not difficult'. CONCLUSION: The ICQ-S is a brief, patient-friendly tool with good reliability and validity, which may be useful for monitoring ICS side-effects in clinical practice.

Airway resistance measurements in pre-school children with asthmatic symptoms: the interrupter technique.

Measuring airway resistance in pre-school children with the interrupter technique has proven to be feasible and reliable in daily clinical practice and research settings. Whether it contributes to diagnosing asthma in pre-school children still remains uncertain. From the results of previous studies a need for standardisation of the technique has emerged. In this overview we will elaborate on research concerning the position of the interrupter technique in the difficult process of diagnosing asthma in pre-school children.

Properties of phosphatidate phosphohydrolase and diacylglycerol acyltransferase activities in the isolated rat heart. Effect of glucagon, ischaemia and diabetes.

Myocardial triacylglycerol hydrolysis is subject to product inhibition. After hydrolysis of endogenous triacylglycerols, the main proportion of the liberated fatty acids is re-esterified to triacylglycerol, indicating the importance of fatty acid re-esterification in the regulation of myocardial triacylglycerol homoeostasis. Therefore, we characterized phosphatidate phosphohydrolase (PAP) and diacylglycerol acyltransferase (DGAT) activities, enzymes catalysing the final steps in the re-esterification of fatty acids to triacylglycerols in the isolated rat heart. The PAP activity was mainly recovered in the microsomal and soluble cell fractions, with an apparent Km of 0.14 mM for both the microsomal and the soluble enzyme. PAP was stimulated by Mg2+ and oleic acid. Oleic acid, like a high concentration of KCl, stimulated the translocation of PAP activity from the soluble to the particulate (microsomal) fraction. Myocardial DGAT had an apparent Km of 3.8 microM and was predominantly recovered in the particulate (microsomal) fraction. Both enzyme activities were significantly increased after acute streptozotocin-induced diabetes, PAP from 15.6 +/- 1.1 to 28.1 +/- 3.6 m-units/g wet wt. (P less than 0.01) and DGAT from 2.23 +/- 0.11 to 3.01 +/- 0.11 m-units/g wet wt. (P less than 0.01). In contrast with diabetes, low-flow ischaemia during 30 min did not affect PAP and DGAT activity in rat hearts. Perfusion with glucagon (0.1 microM) during 30 min did not affect total PAP activity, but changed the subcellular distribution. More PAP activity was recovered in the particulate fraction. DGAT activity was lowered by glucagon treatment from 0.37 +/- 0.03 to 0.23 +/- 0.02 m-unit/mg of microsomal protein (P less than 0.05). The role of PAP and DGAT activity and PAP distribution in the myocardial glucose/fatty acid cycle is discussed.

Involvement of lysosome-like particles in the metabolism of endogenous myocardial triglycerides during ischemia/reperfusion. Uptake and degradation of triglycerides by lysosomes isolated from rat heart.

The hormonal regulation and enzymatic basis of endogenous lipolysis in heart are not yet completely elucidated. The lysosomal fraction from rat heart appeared to be markedly enriched in triglycerides and a significant reduction in triglycerides in this fraction was found after prolonged perfusion or stimulation of lipolysis with glucagon. The enhanced rate of lipolysis, measured as glycerol release from the isolated perfused rat heart, was abolished 10-15 min after continuous glucagon administration. Omission of glucagon for another 60 min restored the ability of glucagon to stimulate lipolysis, indicating the limited availability of endogenous triglycerides and the presence of a transfer-system for triglycerides from a non-metabolically active pool to a metabolically active pool. The enhanced lipolysis induced by low-flow ischemia was found to be inhibited by the lysosomotropic agent methylamine (5 mM). Methylamine-perfusion during low-flow ischemia was accompanied by an increased recovery of myocardial triglycerides in the lysosomal fraction. The possible role of lysosome-like particles in myocardial triglyceride homeostasis was further investigated by studying the kinetics of uptake and degradation of labeled triglycerides by membrane-particles recovered in the subcellular fraction enriched with lysosomal marker enzymes. It appeared that isolated lysosomal membranes take up added triglycerides at an average rate of 30 nmoles/min/g protein. The bulk of these triglycerides taken up is stored whereas 20% is degraded to diglycerides and free fatty acids. More than 90% of the free fatty acids formed were released from the lysosomes into the supernatant. The uptake and degradation of triglyceride-filled liposomes by isolated myocardial lysosomes was inhibited during incubation with methylamine (5 mM). On the other hand, a lowering of pH during in vitro incubation increased the rate of uptake and degradation of added triglycerides by isolated lysosomes. These results indicate that lysosomes or lysosome-like particles are involved in the enhanced lipolysis during myocardial ischemia.

Enhanced lipolysis of myocardial triglycerides during low-flow ischemia and anoxia in the isolated rat heart.

We studied lipolysis in the isolated rat heart, measured as glycerol release during anoxia, low-flow ischemia and subsequent reperfusion. It was found that the rate of lipolysis was enhanced during ischemia/anoxia while the lipase activities in tissue extracts involved in the myocardial lipolysis and the amount of triglycerides were not affected. This indicates the dominant occurrence of a lipolysis-reesterification principle in ischemic and anoxic tissue. A common observation of ischemia/anoxia is an increase in the tissue NADH/NAD+ ratio. Therefore we investigated the effect of lactate and malate, both of which enhance the tissue redox state on myocardial lipolysis. Perfusion in the presence of lactate (10 mM) and malate (10 mM) both stimulated myocardial lipolysis by about five times. This suggests that the rate of reesterification of product fatty acids to triglycerides, which is determined by the NADH/NAD+ ratio, because of the increased formation of glycerol 3-phosphate from dihydroxy acetone phosphate, plays an important role in the regulation of lipolysis. The existence of triglyceride-fatty acid-triglyceride cycle is discussed.

Cholesteryl esterase activities in ventricles, isolated heart cells and aorta of the rat.

Cholesteryl esterase activities were determined in homogenates of rat heart (ventricles), isolated, calcium-tolerant, cardiac myocytes and aortic tissue and were compared with acid and neutral triglyceride lipase activities in these fractions. Using cholesteryl oleate/phosphatidylcholine/taurocholate emulsions and digitonin pretreatment of the enzyme fractions, acid and neutral cholesteryl esterase activities were measured in all tissue preparations. In contrast to the acid and neutral triglyceridase and acid cholesteryl esterase activity, the neutral cholesteryl esterase activity was subject to substrate inhibition. Upon isolation of cardiac myocytes, and in contrast with the recovery of neutral triglyceride lipase activity, only a small portion of the neutral cholesteryl esterase (6%) was recovered, suggesting that nonmyocyte neutral cholesteryl esterase activity markedly contributes to the relatively high activity detectable in whole ventricular homogenates. The recovery of large amounts of neutral cholesteryl esterase activity in the supernatant of collagenase-digested heart tissue, obtained during the isolation of myocytes, which is also markedly enriched in activities of two endothelial marker enzymes (5'-nucleotidase and angiotensine-converting enzyme) may indicate the predominant contribution of neutral cholesteryl esterase activity from coronary endothelial cells to this activity detectable in ventricular homogenates. Relative to the activity in ventricular and myocyte homogenates, aorta homogenates possessed the highest specific neutral cholesteryl esterase activity. We propose that in addition to coronary endothelium, smooth muscle cells also contribute to the neutral cholesteryl esterase activity in ventricular homogenates.(ABSTRACT TRUNCATED AT 250 WORDS)

Stimulation of myocardial neutral triglyceride lipase activity by adenosine-3':5'-monophosphate: involvement of glycogenolysis.

Endogenous lipolysis can be influenced by various hormones. Hormonal stimulation of endogenous lipolysis in the Langendorff heart was diminished by inhibition of glycogenolysis. Therefore we studied the influence of glycogenolysis on the cAMP-dependent activation of the neutral triglyceride lipase activity using a 40,000 X g post mitochondrial supernatant fraction from rat heart homogenates. In the presence of cAMP and ATP neutral triglyceride lipase activity was stimulated by 40%. This stimulation could not be detected in supernatants from which glycogen was removed after incubation in the presence of amyloglucosidase. Addition of glycogen overcomes this loss of stimulation. The activation of neutral triglyceride lipase by cAMP and ATP was mimicked by glucose plus ATP as well as by glycerol-3-phosphate but not by glyceraldehyde-3-phosphate. Moreover, the cAMP stimulation of neutral triglyceride lipase activity was suppressed by low amounts of palmitoyl-CoA indicating product inhibition of lipase activity. These results indicate that the level of intracellular precursors of fatty acid re-esterification, by determining the removal rate of product fatty acids, may be the major determinant of the stimulation of lipolysis by cAMP.

Characterization of mono-, di- and triacylglycerol lipase activities in the isolated rat heart.

The lipolytic activities of heart tissue towards full and partial acylglycerols were characterized. Tissue lysosomal, acid lipase activity (pH 4.8) was inhibited by high salt, protamine sulfate, NaF, MgATP, Triton X-100, serum and the esterase-inhibitor diethylparanitrophenyl phosphate. The tissue neutral triacylglycerol lipase activity (pH 7.4) was recovered predominantly in the microsomal and soluble fractions and exhibited essentially identical properties towards activators (serum, apolipoprotein C-II) and reagents (NaCl, Triton X-100, NaF, MgATP and diethylparanitrophenyl phosphate) relative to vascular lipoprotein lipase, except for protamine sulfate which increased the serum-stimulated neutral triacylglycerol lipase activity. Triacylglycerol hydrolysis at acid pH was incomplete, whereas at neutral pH full hydrolysis occurred. Myocardial mono- and diacylglycerol lipase activities, with pH optima of 8.0 and 7.4, respectively, were recovered in the microsomal fraction. They differed immunologically from neutral lipase and lipoprotein lipase and did not bind to heparin-Sepharose 4B. They were kinetically different, partially inhibited by NaCl and differentially affected by protamine sulfate. NaF, Triton X-100 and diethylparanitrophenyl phosphate. Our data suggest that endogenous hydrolytic activity against full and partial acylglycerols is mediated by separate enzymes.

Studies on the involvement of lipolytic enzymes in endogenous lipolysis of the isolated rat heart.

Rat hearts were depleted in vivo from both the heparin-releasable lipoprotein lipase and heparin-resistant tissue neutral triacylglycerol lipase activity by treatment of the animals with cycloheximide (2 mg/kg body weight), intraperitoneally injected 2.5 and 5 h prior to perfusion. The tissue acid lipase, mono- and diacylglycerol lipase activities were not affected by cycloheximide-induced inhibition of protein synthesis. Myocardial basal and glucagon-stimulated lipolysis, determined by the rate of glycerol production and release from the isolated hearts, was not significantly different in control and cycloheximide-treated rats. Tissue triacylglycerols were recovered with the highest relative specific distribution in the lysosomal fraction isolated from heart homogenates. Upon prolongation of the perfusion-duration the relative specific distribution of triacylglycerols in the lysosomal fraction decreased. In addition, the specific lysosomal triacylglycerol content (micrograms/mg protein) dropped significantly, indicating an important role of lysosomes in myocardial triacylglycerol turnover. Our data strongly suggest that the heparin-resistant neutral triacylglycerol lipase activity may not be the only determinant of endogenous lipolysis in the isolated rat heart and indicate that lipolysis may additionally be mediated by the lysosomal, acid lipase in concert with the microsomal mono-and diacylglycerol lipase.