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Biomedical subjects

A van der Laarse

Publications and source records attributed to A van der Laarse.

At least 19 recordsLinked to original sources
PubMed2001

The role of angiotensin II, endothelin-1 and transforming growth factor-beta as autocrine/paracrine mediators of stretch-induced cardiomyocyte hypertrophy.

Cardiac hypertrophy is a compensatory response of myocardial tissue upon increased mechanical load. Of the mechanical factors, stretch is rapidly followed by hypertrophic responses. We tried to elucidate the role of angiotensin II (AII), endothelin-1 (ET-1) and transforming growth factor-beta (TGF-beta) as autocrine/paracrine mediators of stretch-induced cardiomyocyte hypertrophy. We collected conditioned medium (CM) from stretched cardiomyocytes and from other stretched cardiac cells, such as cardiac fibroblasts, endothelial cells and vascular smooth muscle cells (VSMCs). These CMs were administered to stationary cardiomyocytes with or without an AII type 1 (AT1) receptor antagonist (losartan), an ET-1 type A (ET(A)) receptor antagonist (BQ610), or anti-TGF-beta antibodies. By measuring the mRNA levels of the proto-oncogene c-fos and the hypertrophy marker gene atrial natriuretic peptide (ANP), the molecular phenotype of the CM-treated stationary cardiomyocytes was characterized. Our results showed that c-fos and ANP expression in stationary cardiomyocytes was increased by All release from cardiomyocytes that had been stretched for 60 min. Stretched cardiomyocytes, cardiac fibroblasts and endothelial cells released ET-1 which led to increased c-fos and ANP expression in stationary cardiomyocytes. ET-1 released by stretched VSMCs, and TGF-beta released by stretched cardiac fibroblasts and endothelial cells, appeared to be paracrine mediators of ANP expression in stationary cardiomyocytes. These results indicate that AII, ET-1 and TGF-beta (released by cardiac and vascular cell types) act as autocrine/paracrine mediators of stretch-induced cardiomyocyte hypertrophy. Therefore, it is likely that in stretched myocardium the cardiomyocytes, cardiac fibroblasts, endothelial cells and VSMCs take part in intercellular interactions contributing to cardiomyocyte hypertrophy.

Angiotensin II↗
PubMed2001

Mechanical stress stimulates phospholipase C activity and intracellular calcium ion levels in neonatal rat cardiomyocytes.

To investigate how mechanical stress is sensed by cardiomyocytes and translated to cardiac hypertrophy, cardiomyocytes were subjected to stretch while measuring phospholipase C (PLC) and phospholipase D (PLD) activities and levels of intracellular calcium ions ([Ca2+]i) and pH. In stretched cardiomyocytes, PLC activity increased 2-fold after 30 min, whereas PLD activity hardly increased at all. Mechanical stress induced by prodding or by cell stretch increased [Ca2+](i)by a factor 5.2 and 4, respectively. Gadolinium chloride (stretch-activated channel blocker) attenuated the prodding-induced and stretch-induced [Ca2+](i)rise by about 50%. Blockade of ryanodine receptors by a combination of Ruthenium Red and procaine reduced the [Ca2+](i)rise only partially. Diltiazem (L-type Ca2+ channel antagonist) blocked the prodding-induced [Ca2+](i)rise completely, and reduced the stretch-induced [Ca2+](i)rise by about 50%. The stretch-induced [Ca2+](i)rise was unaffected by U73122, an inhibitor of PLC activity. Stretch did not cause cellular alkalinization. In conclusion, in cardiomyocytes, PLC and [Ca2+](i)levels are involved in the stretch-induced signal transduction, whereas PLD plays apparently no role. The stretch-induced rise in [Ca2+](i)in cardiomyocytes is most probably caused by [Ca2+](i)influx through L-type Ca2+ channels and stretch-activated channels, leading to Ca2+-induced Ca2+ -release from the SR via the ryanodine receptor.

Anesthetics, Local↗
PubMed2001

Direct, autocrine and paracrine effects of cyclic stretch on growth of myocytes and fibroblasts isolated from neonatal rat ventricles.

Several studies have demonstrated that static stretch of cardiomyocytes induces cardiomyocyte hypertrophy. We investigated the effects of cyclic stretch, a more physiological stimulus, on protein synthesis and DNA synthesis of rat ventricular cardiomyocytes and cardiofibroblasts. Further-more, we investigated whether these effects are caused by autocrine mechanisms. In addition, we studied the paracrine influences of stretched cardiofibroblasts on cardiomyocyte growth. Short-term cyclic stretch (0-24 h) of cardiomyocytes induced a growth response indicative of cardiomyocyte hypertrophy, given the fact that increased rates of protein synthesis and DNA synthesis were accompanied by an elevated release of atrial natriuretic peptide into the culture medium. In cardiofibroblasts, short-term cyclic stretch also induced a growth response as indicated by an increased rate of protein synthesis and DNA synthesis. Furthermore, incubation of stationary cardiofibroblasts with conditioned medium derived from stretched cardiofibroblasts revealed an autocrine effect of stretch as illustrated by an increased rate of protein synthesis in stationary cardiofibroblasts. In analogy, there was an autocrine effect of stretch on stationary cardiomyocytes incubated with conditioned medium derived from stretched cardiomyocytes. Moreover, we observed a paracrine effect of the conditioned medium derived from stretched cardiofibroblasts on stationary cardiomyocytes. Thus, short-term cyclic stretch of cardiomyocytes and cardiofibroblasts induces growth responses that are the result of direct, autocrine, and paracrine effects. These autocrine/paracrine effects of stretch are most probably due to release of factors from stretched cells.

Animals↗
PubMed2001

Bezafibrate reduces heart rate and blood pressure in patients with hypertriglyceridemia.

OBJECTIVE: In hypertriglyceridemic patients, hypertension occurs frequently and may be associated with hyperinsulinemia and elevated plasma levels of free fatty acids (FFA). Besides the lipid-lowering effects, fibrates have been shown to reduce blood pressure in hypertensive patients. The present study was undertaken to investigate the effects of bezafibrate on hemodynamics in relation to insulin, FFA, sympathetic activity, renal sodium absorption, cyclic-GMP (cGMP) and endothelin-1 in hypertriglyceridemic patients. SUBJECTS AND METHODS: Hypertriglyceridemic patients (17) were randomized to receive in a double-blind placebo-controlled study bezafibrate or placebo for 6 weeks. At the end of both treatment periods, blood pressure and heart rate were measured automatically. Plasma insulin, FFA, aldosterone, catecholamines, cGMP, endothelin-1 levels and 24 h urine catecholamines and sodium excretion were assessed. RESULTS: Bezafibrate therapy decreased serum triglycerides (-65%, P < 0.001) and hemodynamic parameters: heart rate decreased from 69 to 66/min (P = 0.009), systolic blood pressure from 137 to 132 mmHg (P = 0.01), diastolic blood pressure from 81 to 79 mmHg (P = 0.07) and mean blood pressure from 102 to 99 mmHg (P = 0.06). Bezafibrate therapy reduced FFA and insulin (-55 and -57% respectively, both P < 0.001), while sympathetic activity and renal sodium absorption were not affected. cGMP increased (+17%, P = 0.008), whereas endothelin-1 levels tended to decrease upon bezafibrate therapy (-10%, P = 0.077) CONCLUSION: Bezafibrate reduces heart rate, blood pressure, insulin and FFA in hypertriglyceridemic patients. The hemodynamic effects cannot be attributed to changes in sympathetic activity or renal sodium absorption. Instead, based on the increase in plasma cGMP levels, the bezafibrate-induced hemodynamic effects are most likely to be caused by bezafibrate-induced improvement of endothelial function.

Absorption↗
PubMed2000

Rapid effects of stretched myocardial and vascular cells on gene expression of neonatal rat cardiomyocytes with emphasis on autocrine and paracrine mechanisms.

Passive stretch of the heart has a direct effect on cardiomyocytes and other cell types including cardiac fibroblasts, endothelial cells, and vascular smooth muscle cells (VSMCs). Cardiomyocytes are targets for the action of peptide growth factors found in myocardium, suggesting an autocrine or paracrine model of the hypertrophic process. In this study we examined stretch-dependent cellular communication between cardiomyocytes, cardiac fibroblasts, endothelial cells, and VSMCs. Stationary cardiomyocytes were incubated with stretch-conditioned medium (CM0-CM60) derived from stretched (for 0-60 min) cardiomyocytes, cardiac fibroblasts, endothelial cells, and VSMCs. The expression levels of protooncogenes (as c-fos, c-jun, and fra-1) were measured, and as an indication of a hypertrophic response the expression of atrial natriuretic peptide (ANP) was measured. Stationary cardiomyocytes that have been incubated for 30 min with CM from stretched (for 0-60 min) cardiomyocytes, cardiac fibroblasts, endothelial cells, and VSMCs showed distinct gene expression patterns that were time-dependent and cell-type specific. In stationary cardiomyocytes, CM derived from stretched cardiomyocytes caused decreased c-fos and fra-1 expression by 37 and 20%, respectively (CM30), elevated c-jun expression by 20% (CM45-CM60), and increased ANP expression by 106% (CM45). CM derived from stretched cardiac fibroblasts caused increased c-fos expression by 41% (CM60), no significant changes in c-jun expression, and increased fra-1 and ANP expression by 39 and 20%, respectively (CM45). CM derived from stretched VSMCs induced an initial decrease in c-fos expression followed by an increase of 13% (CM45) and induced increased c-jun, fra-1, and ANP expression by 39, 24, and 22%, respectively. CM15-CM60 derived from stretched endothelial cells caused decreased c-fos, c-jun and fra-1 expression by 20, 25, and 25%, respectively, and increased ANP expression by 18%. Our data indicate that gene expression of cardiomyocytes in stretched myocardium is regulated by mediators released by cardiomyocytes, cardiac fibroblasts, endothelial cells, and VSMCs. This observation emphasizes the involvement of nonmyocyte cells in the early stages of cardiomyocyte hypertrophy caused by cardiac stretch.

Animals↗
PubMed2000

In vivo determination of the molecular composition of artery wall by intravascular Raman spectroscopy.

Atherosclerotic plaque vulnerability is suggested to be determined by its chemical composition. However, at present there are no in vivo techniques available that can adequately type atherosclerotic plaques in terms of chemical composition. Previous in vitro experiments have shown that Raman spectroscopy can provide such information in great detail. Here we present the results of in vitro and in vivo intravascular Raman spectroscopic experiments, in which dedicated, miniaturized fiber-optic probes were used to illuminate the blood vessel wall and to collect Raman scattered light. The results make clear that an important hurdle to clinical application of Raman spectroscopy in atherosclerosis has been overcome, namely, the ability to obtain in vivo intravascular Raman spectra of high quality. Of equal importance is the finding that the in vivo intravascular Raman signal obtained from a blood vessel is a simple summation of signal contributions of the blood vessel wall and of blood. It means that detailed information about the chemical composition of a blood vessel wall can be obtained by adapting a multiple least-squares fitting method, which was developed previously for the analysis of in vitro spectra, to account for signal contributions of blood.

Animals↗
PubMed2000

Adenovirus-based phospholamban antisense expression as a novel approach to improve cardiac contractile dysfunction: comparison of a constitutive viral versus an endothelin-1-responsive cardiac promoter.

BACKGROUND: A decrease in sarcoplasmic reticulum Ca(2+) pump (SERCA2) activity is believed to play a role in the impairment of diastolic function of the failing heart. Because the expression ratio of phospholamban (PL) to SERCA2 may be a target to improve contractile dysfunction, a PL antisense RNA strategy was developed under the control of either a constitutive cytomegalovirus (CMV) or an inducible atrial natriuretic factor (ANF) promoter. The latter is upregulated in hypertrophied and failing heart, allowing "induction-by-disease" gene therapy. METHODS AND RESULTS: Part of the PL cDNA was cloned in antisense and sense directions into adenovectors under the control of either a CMV (Ad5CMVPLas and Ad5CMVPLs, respectively) or ANF (Ad5ANFPLas and Ad5ANFPLs, respectively) promoter. Infection of cultured rat neonatal cardiomyocytes with Ad5CMVPLas reduced PL mRNA to 30+/-7% of baseline and PL protein to 24+/-3% within 48 and 72 hours, respectively. The effects were vector dose dependent. Ad5CMVPLas increased the Ca(2+) sensitivity of SERCA2 and reduced the time to 50% recovery of the Ca(2+) transient. A decrease of PL protein was also achieved by infection with Ad5ANFPLas, and the presence of the hypertrophic stimulus, endothelin-1, led to enhanced downregulation of PL. The adenovectors expressing PL sense RNA had no effect on any of the tested parameters. CONCLUSIONS: Vector-mediated PL antisense RNA expression may become a feasible approach to modulate myocyte Ca(2+) homeostasis in the failing heart. The inducible ANF promoter for the first time offers the perspective for induction-by-disease gene therapy, ie, selective expression of therapeutic genes in hypertrophied and failing cardiomyocytes.

Adenoviridae↗
PubMed2000

The athlete's heart. A meta-analysis of cardiac structure and function.

BACKGROUND: It has been postulated that depending on the type of exercise performed, 2 different morphological forms of athlete's heart may be distinguished: a strength-trained heart and an endurance-trained heart. Individual studies have not tested this hypothesis satisfactorily. METHODS AND RESULTS: The hypothesis of divergent cardiac adaptations in endurance-trained and strength-trained athletes was tested by applying meta-analytical techniques with the assumption of a random study effects model incorporating all published echocardiographic data on structure and function of male athletes engaged in purely dynamic (running) or static (weight lifting, power lifting, bodybuilding, throwing, wrestling) sports and combined dynamic and static sports (cycling and rowing). The analysis encompassed 59 studies and 1451 athletes. The overall mean relative left ventricular wall thickness of control subjects (0.36 mm) was significantly smaller than that of endurance-trained athletes (0.39 mm, P=0.001), combined endurance- and strength-trained athletes (0.40 mm, P=0.001), or strength-trained athletes (0.44 mm, P<0.001). There was a significant difference between the 3 groups of athletes and control subjects with respect to left ventricular internal diameter (P<0. 001), posterior wall thickness (P<0.001), and interventricular septum thickness (P<0.001). In addition, endurance-trained athletes and strength-trained athletes differed significantly with respect to mean relative wall thickness (0.39 versus 0.44, P=0.006) and interventricular septum thickness (10.5 versus 11.8 mm, P=0.005) and showed a trend toward a difference with respect to posterior wall thickness (10.3 versus 11.0 mm, P=0.078) and left ventricular internal diameter (53.7 versus 52.1 mm, P=0.055). With respect to cardiac function, there were no significant differences between athletes and control subjects in left ventricular ejection fraction, fractional shortening, and E/A ratio. CONCLUSIONS: Results of this meta-analysis regarding athlete's heart confirm the hypothesis of divergent cardiac adaptations in dynamic and static sports. Overall, athlete's heart demonstrated normal systolic and diastolic cardiac functions.

Adult↗
PubMed2000

Myocardial enzyme activities in plasma after whole-heart irradiation in rats.

Plasma levels of myocardial enzymes present after local heart irradiation were studied in a rat model. The purpose was to investigate whether, within days after irradiation, these enzyme levels change to such an extent that they may be helpful in assessing the severity of cardiac damage after radiotherapy. Therefore, activities of creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alpha-hydroxybutyrate dehydrogenase (alpha-HBDH) were determined in the plasma and left ventricular myocardium of rats following local heart irradiation with a single dose of 20 Gy. A dose of 20 Gy is known to cause irreversible cardiac damage and to reduce survival times of the animals. Cardiac enzyme assays were performed directly after and twice daily for up to 2 weeks after radiation. Plasma CK, LDH, AST and alpha-HBDH levels were increased between 2 h and 24 h after irradiation. Plasma ALT levels remained unchanged. Myocardial enzyme levels, measured between 24 h and 16 days after radiation, did not differ between irradiated and control animals, although acute (first 12 h) reductions were observed in the irradiated group. The elevated enzyme levels in plasma appeared to correlate with the acutely reduced myocardial enzyme levels. Although irradiation with a dose of 20 Gy induced acute rises of cardiac enzyme levels in plasma, it is doubtful that fractionated radiation, as applied clinically for treatment of solid tumors, will induce plasma enzyme elevations that are large enough to indicate the extent of cardiac damage occurring acutely or chronically.

Alanine Transaminase↗
PubMed2000

Rapid gene transcription induced by stretch in cardiac myocytes and fibroblasts and their paracrine influence on stationary myocytes and fibroblasts.

Functional adaptation of cardiac cells in response to haemodynamic load requires dynamic alteration of gene expression. In this study, we examined early changes in gene expression following stretch in myocytes and fibroblasts isolated from neonatal rat hearts. In the first hour of biaxially applied static stretch, the changes in expression of immediate-early genes, such as c-fos, c-jun and fra-1, were quantified. The expression of the atrial natriuretic peptide (ANP) gene in myocytes was measured as an indication of the hypertrophic response. In stretched myocytes, expression of c-fos and ANP increased transiently to 227% and 176% respectively after 30 min stretch, whereas c-jun and fra-1 expression decreased in the 1st hour of stretch. In stretched fibroblasts the expression of c-fos and fra-1 increased transiently to maxima of 145% and 146% respectively after 30 min stretch, whereas c-jun expression did not change significantly. To study the indirect effects of stretch, as an indication of cross-talk between cardiac cells, stationary myocytes and fibroblasts were incubated with stretch-conditioned medium (CM) from stretched (0-60 min) myocytes and fibroblasts. CM from stretched myocytes reduced c-fos and induced c-jun expression in myocytes and fibroblasts, reduced fra-1 expression in myocytes but induced fra-1 expression in fibroblasts. CM from stretched fibroblasts induced c-fos expression and had little effect on c-jun expression in myocytes and fibroblasts, induced the fra-1 expression in myocytes but had little effect on fra-1 expression in fibroblasts. CM from myocytes and CM from fibroblasts induced ANP expression in myocytes to 206% and 120% respectively after 45 min stretch. Static stretch of myocytes and fibroblasts appears to stimulate, within 1 h, secretion of cell type-specific factors that participate in the regulation of proto-oncogene and ANP expression of stationary myocytes and fibroblasts. These early changes in gene transcription suggest that stretch of the myocardium initiates intracellular gene expression as well as cross-talk between the cell types.

Animals↗
PubMed2000

Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways.

Cardiac hypertrophy is a well known response to increased hemodynamic load. Mechanical stress is considered to be the trigger inducing a growth response in the overloaded myocardium. Furthermore, mechanical stress induces the release of growth-promoting factors, such as angiotensin II, endothelin-1, and transforming growth factor-beta, which provide a second line of growth induction. In this review, we will focus on the primary effects of mechanical stress: how mechanical stress may be sensed, and which signal transduction pathways may couple mechanical stress to modulation of gene expression, and to increased protein synthesis. Mechanical stress may be coupled to intracellular signals that are responsible for the hypertrophic response via integrins and the cytoskeleton or via sarcolemmal proteins, such as phospholipases, ion channels and ion exchangers. The signal transduction pathways that may be involved belong to two groups: (1) the mitogen-activated protein kinases (MAPK) pathway; and (2) the janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. The MAPK pathway can be subdivided into the extracellular-regulated kinase (ERK), the c-Jun N-terminal kinase (JNK), and the 38-kDa MAPK (p38 MAPK) pathway. Alternatively, the stress signal may be directly submitted to the nucleus via the cytoskeleton without the involvement of signal transduction pathways. Finally, by promoting an increase in intracellular Ca2+ concentration stretch may stimulate the calcium/calmodulin-dependent phosphatase calcineurin, a novel hypertrophic signalling pathway.

Cardiomegaly↗
PubMed2000

The hypolipidemic action of bezafibrate therapy in hypertriglyceridemia is mediated by upregulation of lipoprotein lipase: no effects on VLDL substrate affinity to lipolysis or LDL receptor binding.

Fibrates are regarded as drugs of choice in hypertriglyceridemia (HTG). Downregulation of apolipoprotein (apo) C-III gene expression and upregulation of lipoprotein lipase (LPL) gene expression have been suggested to explain the hypolipidemic action of fibrates. This study was designed to study the effects of bezafibrate therapy on very low density lipoprotein (VLDL) susceptibility to lipolysis, VLDL binding to the low density lipoprotein (LDL) receptor and postheparin LPL activities in patients with HTG. VLDL lipolysis was studied with heparan sulfate proteoglycan-bound LPL. Binding affinity of VLDL to the LDL receptor was determined in J774 cells with 125I-labeled control LDL. Eighteen HTG patients were randomized to receive, in a double-blind placebo-controlled cross-over fashion, 400 mg bezafibrate once daily for 6 weeks. In response to bezafibrate therapy, plasma triglyceride and apoC-III levels decreased by 69 and 42%, respectively. HTG VLDL was lipolyzed less efficiently compared to control VLDL, and lipolysis did not improve by bezafibrate therapy. VLDL binding affinity to the LDL receptor was comparable between the control group and HTG group, and did not change upon bezafibrate therapy. However, the post-heparin LPL activity in the HTG patients increased from 153 to 192 U/l (P = 0.025). A strong inverse relation was observed between the change in LPL activities and the change in triglyceride levels (r = -0.62, P = 0.006). In conclusion, the hypolipidemic action of bezafibrate therapy in HTG may be attributed to increased LPL activity, whereas VLDL susceptibility to lipolysis and LDL receptor binding are not affected.

Adult↗
PubMed2000

Activated platelets in patients with severe hypertriglyceridemia: effects of triglyceride-lowering therapy.

Hypertriglyceridemia, a risk factor for cardiovascular disease, has been associated with hypercoagulability, but whether platelet activation is implicated is unknown. This study was designed to compare the in vivo platelet activation status between patients with severe hypertriglyceridemia and age- and sex-matched control subjects, and to evaluate the effects of triglyceride-lowering therapy. Sixteen patients with primary hypertriglyceridemia were included in a double-blind, placebo-controlled cross-over trial with 400 mg bezafibrate once daily. Platelet activation was analysed by double label flow cytometry, using monoclonal antibodies against GP53, P-selectin, and platelet-bound fibrinogen. Surface expression of the lysosomal membrane protein GP53 was significantly higher in the hypertriglyceridemic patients at baseline as compared to the group of age- and sex-matched controls (16.3+/-4.8% vs. 8.9+/-3.4%, respectively, P<0.001). No differences in the expression of P-selectin and fibrinogen binding were observed. In response to bezafibrate therapy, the expression of GP53 in the patient group decreased from 16.3+/-4.8% to 13.1+/-4.1% (P=0.018). The expression of P-selectin and fibrinogen binding was not affected by bezafibrate therapy. In conclusion, patients with hypertriglyceridemia have an increased in vivo platelet activation status, which can be improved by bezafibrate therapy.

Antigens, CD↗
PubMed2000

Cyclic stretch induces the release of growth promoting factors from cultured neonatal cardiomyocytes and cardiac fibroblasts.

Growth factors and hormones may play an autocrine/paracrine role in mechanical stress-induced cardiac hypertrophy. Using an in vitro model of mechanical stress, i.e. stretch of cardiomyocytes and cardiac fibroblasts, we tested the involvement of growth factors and hormones in this process. We found that conditioned medium (CM) derived from 4 h cyclicly (1 Hz) stretched cardiomyocytes increased the rate of protein synthesis in static cardiomyocytes by 8 +/- 3%. Moreover, CM derived from 2 h stretched fibroblasts increased the rate of protein synthesis in static fibroblasts as well as in static cardiomyocytes by 8 +/- 2 and 6 +/- 2%, respectively. Analysis of CM using size-exclusion HPLC showed that cardiomyocytes and fibroblasts released at least three factors with MW < or = 10 kD, their quantities being time-dependently increased by stretch. Subsequent analyses using immunoassays revealed that cardiomyocytes released atrial natriuretic peptide (ANP) and transforming growth factor-beta1 (TGFbeta1) being increased by 45 +/- 17 and 21 +/- 4% upon 4 h of stretch, respectively. Fibroblasts released TGFbeta1 and very low quantity of endothelin-1 (ET-1). The release of TGFbeta1 was significantly increased by 18 +/- 4% after 24 h of stretch in fibroblasts. Both cell types released no detectable amount of angiotensin II (Ang II). In conclusion, upon cyclic stretch cardiomyocytes and fibroblasts secrete growth factors and hormones which induce growth responses in cardiomyocytes and fibroblasts in an autocrine/paracrine way. TGFbeta secreted by cardiomyocytes and fibroblasts, and ANP secreted by cardiomyocytes are likely candidates. We found no evidence for the involvement of Ang II and ET-1 in autocrine/paracrine mechanisms between cardiac cell types.

Animals↗
PubMed2000

Intravascular ultrasound combined with Raman spectroscopy to localize and quantify cholesterol and calcium salts in atherosclerotic coronary arteries.

Coronary intravascular ultrasound (IVUS) can assess arterial wall architecture and localize large intravascular deposits, but it does not provide quantitative chemical information, which is essential in the evaluation of atherosclerotic lesions. Previously, it has been shown that Raman spectroscopy can be used to accurately quantify the relative weights of cholesterol, calcium salts, triglycerides, and phospholipids in homogenized arterial tissue. In the present study, we explore some benefits of combining IVUS and Raman spectroscopy to evaluate the intact arterial wall. IVUS images were collected in vitro from human coronary arterial segments in various stages of disease (n=7). The images were divided into radial segments (11 to 28 per image, 332 in total), each of which was classified visually as calcified or noncalcified tissue. The arteries were opened longitudinally, and Raman spectra were collected from locations at 0. 5-mm intervals across the arterial luminal circumference. The spectra were used to calculate the chemical composition of the arterial wall at the examined locations. Generally, locations containing large amounts of calcium salts, as determined with Raman spectroscopy, were classified as calcified with IVUS. However, small calcific deposits (<6% of weight) were not readily detected with IVUS. The amounts and location of cholesterol determined with Raman spectroscopy were correlated closely with the presence of cholesterol observed by histochemistry, but these deposits could not be located accurately by IVUS. The combination of Raman spectroscopy and IVUS applied in vitro provides detailed information about the amount and location of calcific deposits and lipid pools in atherosclerotic plaques. Future advances in optical fiber technology may allow simultaneous collection of Raman spectra and IVUS images through the same catheter in vivo.

Adult↗
PubMed2000

Not acute but chronic hypertriglyceridemia is associated with impaired endothelium-dependent vasodilation: reversal after lipid-lowering therapy by atorvastatin.

There is controversy regarding the relation between hypertriglyceridemia (HTG) and endothelial function. This study was designed to investigate endothelial function in a patient group with chronic HTG, before and during lipid-lowering therapy by atorvastatin. In addition, the effects of acute HTG on endothelial function were studied in normolipidemic individuals. Eight male patients with chronic HTG were studied before and after 6 weeks of lipid-lowering treatment with 80 mg atorvastatin once daily. Ten age-matched control subjects were studied at baseline and immediately after a high-dose infusion of artificial triglycerides. The endothelium-dependent response to serotonin was attenuated in the HTG group, whereas the response to acetylcholine was comparable to the response in the control group. The response to the endothelium-independent vasodilator nitroprusside was comparable in both groups. In response to atorvastatin therapy, serum triglyceride and cholesterol levels decreased significantly by 43% (paired t test, P=0.017) and 38% (paired t test, P=0.012), respectively. After 6 weeks of treatment, the forearm blood flow response to serotonin improved from 63% to 106% (ANOVA, P<0.001). Induction of acute HTG in the control subjects did not affect the forearm blood flow responses to serotonin and nitroprusside; however, the response to acetylcholine was paradoxically increased. In conclusion, patients with chronic HTG have an impaired endothelium-dependent vasodilation to serotonin that is normalized after 6 weeks of lipid-lowering therapy by atorvastatin.

Acetylcholine↗
PubMed1999

Diastolic dysfunction in hypertensive heart disease is associated with altered myocardial metabolism.

BACKGROUND: Hypertension is an important clinical problem and is often accompanied by left ventricular (LV) hypertrophy and dysfunction. Whether the myocardial high-energy phosphate (HEP) metabolism is altered in human hypertensive heart disease and whether this is associated with LV dysfunction is not known. METHODS AND RESULTS: Eleven patients with hypertension and 13 age-matched healthy subjects were studied with magnetic resonance imaging at rest and with phosphorus-31 magnetic resonance spectroscopy at rest and during high-dose atropine-dobutamine stress. Hypertensive patients showed higher LV mass (98+/-28 g/m2) than healthy control subjects (73+/-13 g/m2, P<0.01). LV filling was impaired in patients, reflected by a decreased peak rate of wall thinning (PRWThn), E/A ratio, early peak filling rate, and early deceleration peak (all P<0. 05), whereas systolic function was still normal. The myocardial phosphocreatine (PCr)/ATP ratio determined in patients at rest (1. 20+/-0.18) and during stress (0.95+/-0.25) was lower than corresponding values obtained from healthy control subjects at rest (1.39+/-0.17, P<0.05) and during stress (1.16+/-0.18, P<0.05). The PCr/ATP ratio correlated significantly with PRWThn (r=-0.55, P<0.01), early deceleration peak (r=-0.56, P<0.01), and with the rate-pressure product (r=-0.53, P<0.001). CONCLUSIONS: Myocardial HEP metabolism is altered in patients with hypertensive heart disease. In addition, there is an association between impaired LV diastolic function and altered myocardial HEP metabolism in humans. The level of myocardial PCr/ATP is most likely determined by the level of cardiac work load.

Adenosine Triphosphate↗