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At least 1,063 records · Page 59Linked to original sources
PubMed1995

Clinical significance of decreased myocardial uptake of 123I-BMIPP in patients with stable effort angina pectoris.

The aim of this study was to assess the feasibility of resting myocardial fatty acid metabolic imaging with 123I-beta-methyliodophenyl-pentadecanoic acid (123I-BMIPP) for the detection of patients with stable effort angina pectoris and to clarify the clinical significance of abnormal 123I-BMIPP images. Myocardial imaging with 123I-BMIPP at rest and 99Tcm-methoxyisobutyl isonitrile (99Tcm-MIBI) at rest and during treadmill exercise was performed in 46 patients with suspected effort angina pectoris. Resting 123I-BMIPP imaging detected 43% (17/40) of patients with significant (> or = 50%) coronary artery stenosis and 59% (17/29) of patients with exercise-induced myocardial ischaemia. The patients with abnormal 123I-BMIPP images terminated exercise after a shorter period (4.5 +/- 2.6 vs 6.7 +/- 4.1 min; P < 0.01) and at a lower rate pressure product (16,124 +/- 5211 vs 20,246 +/- 6564 mmHg x beats min-1; P < 0.01) than those with normal 123I-BMIPP images. The presence of ST depression during the exercise test (77 vs 52%; P < 0.05), severe coronary stenosis exceeding 90% (88 vs 43%; P < 0.01), collateral vessels (35 vs 9%; P < 0.01) and a wall motion abnormality of hypokinesis/akinesis (53 vs 30%; P < 0.05) were more frequently seen in patients with abnormal 123I-BMIPP images than in those with normal images. Resting 123I-BMIPP imaging was able to detect the presence of coronary artery stenosis and exercise-induced myocardial ischaemia with moderate sensitivity, and to determine the functional severity of coronary artery disease.

Angina Pectoris↗
PubMed1993

Modulation of multidrug resistance gene expression by dexamethasone in cultured hepatoma cells.

Considerable evidence has accumulated indicating that overexpression of P-glycoproteins encoded by the multidrug-resistance (mdr) genes is responsible for the development of collateral resistance to a number of structurally and functionally dissimilar cytotoxic compounds in animal cells. There are three mdr genes (mdr1, mdr2, and mdr3) in the mouse genome and two (MDR1 and MDR2) in the human genome; however, only two mouse genes (mdr1 and mdr3) and one human gene (MDR1) can confer multidrug resistance upon transfection into otherwise drug-sensitive cells. Using RNase protection assay we report here that the steady-state levels of mdr1 and mdr3 messenger RNA were elevated in mouse hepatoma cells treated with dexamethasone (Dex); whereas no induction of mdr2 gene was found. Western blot analyses using anti-mdr1 and anti-mdr3 antibodies revealed that the encoded proteins appeared to be increased, but at much reduced levels. The induction was time and Dex concentration dependent. Nuclear run-on experiments demonstrated that the induction was at least in part by transcriptional control. The induction apparently required new protein synthesis since no increases in mdr1 and mdr3 transcripts was found when cultured cells were simultaneously treated with Dex and cycloheximide. Neither mdr1 nor mdr3 gene was induced in the Dex-treated nonhepatoma cell lines, LMtk- and NIH3T3. Similarly, MDR1 messenger RNA levels were elevated in the Dex-treated human hepatoma line, HepG2, but not in the nonhepatoma, HeLa. This study demonstrated that the hormonal regulation of mdr gene expression is gene and cell type specific.

3T3 Cells↗
PubMedDate not supplied

Carbamylated erythropoietin reduces radiosurgically-induced brain injury.

Gamma knife radiosurgery is an attractive noninvasive treatment of brain tumors and vascular malformations that minimizes collateral tissue damage. However, exposure of normal tissue to even low-dose radiation triggers a cascade of acute and chronic injury and potentially significant morbidity and mortality. Because many irradiated patients now survive for years, identifying methods to prevent radiotherapy-induced collateral tissue damage is a major focus of current research. Erythropoietin (EPO), a cytokine produced locally by many tissues in response to injury, antagonizes apoptosis, reduces inflammation, and promotes healing. Systemic administration of recombinant EPO, widely used for treatment of anemia, provides robust protection from numerous insults in a variety of tissues, including the brain. Although irradiation injury is likely sensitive to EPO, the hematopoietic activity of EPO is undesirable in this setting, increasing erythrocyte number and predisposing to thrombosis. To avoid these potential adverse effects, we developed carbamylated EPO (CEPO) which does not stimulate the bone marrow. In this study, we show that CEPO (50 microg kg(-1) intraperitoneally) improves functional outcome when administered to adult rats just before, and then once daily for 10 d after, a necrotizing dose of radiation (100 Gy) to the right striatum. Immediately following irradiation, use and reflex movements of the contralateral forelimb to vibrissae stimulation were abnormal but rapidly improved in animals receiving CEPO. Moreover, histological examination revealed that the extent of brain necrosis after 90 days was reduced by approximately 50%. These findings further extend the kinds of injury for which administration of a tissue-protective cytokine provides benefit.

Animals↗
PubMed2001

[Modern diagnostic concepts in dissection and aortic occlusion].

For the diagnostic work-up of the aorta, non-invasive cross-sectional imaging techniques have almost replaced invasive catheter angiography. CT- and MR-angiography are supplemented by sonography which is used predominantly for the assessment of abdominal aortic aneurysm and dissections of the thoracic aorta. This review deals with the diagnostic approach to two disease entities involving the aorta: aortic dissection and aortic occlusion. Transoesophageal echocardiography (TEE), CT- and MR-angiography (MRA) are used in the assessment of aortic dissection. Published sensitivity and specificity values regarding the detection and classification of dissections into Stanford A and Stanford B range between 96-100% for all three modalities. Results for multislice CTA have not yet been reported, but can be expected to be at least as good. The ability to delineate additional information regarding the precise morphology of true and false lumen, entry and reentry-sites, the development of thrombus or paraaortic hematomas, as well as the assessment of aortic regurgitation or involvement of coronary arteries depend on the chosen technique. Reflecting the ability to collect functional imaging data, both TEE and MRA are superior to CTA in the assessment of aortic valve involvement, while TEE is the modality of choice for evaluation of coronary arteries. Sonography is of limited use in the assessment of abdominal dissections. For the evaluation of patients with suspected aortic occlusion both CTA and MRA represent the imaging modalities of choice. Both provide for a comprehensive and precise depiction of the underlying aortic morphology, the extent of collateral flow as well as delineation of distal run-off vessels. MRA should be employed in patients with impaired renal function as paramagnetic contrast agents are not nephrotoxic.

Aged↗
PubMed1995

Significance of ST segment depression during adenosine-induced coronary hyperemia in angina pectoris and correlation with angiographic, scintigraphic, hemodynamic, and echocardiographic variables.

Factors determining myocardial ischemia during adenosine-induced coronary vasodilation in patients with angina pectoris are not well defined. To evaluate the angiographic, scintigraphic, hemodynamic, and echocardiographic determinants of ST segment depression during adenosine infusion, 40 patients with angina pectoris underwent technetium-99m sestamibi single photon emission computed tomography and simultaneous two-dimensional echocardiography. Ischemic ST depression occurred in 18 patients (45%). Coronary angiography was performed in all patients and a coronary artery jeopardy score was determined. The sensitivity, specificity, and the predictive accuracy of adenosine-induced ST segment depression in detecting significant coronary artery disease were 53%, 100%, and 60%, respectively, while the corresponding results for detecting reversible perfusion defects were 61%, 92%, and 70%, respectively. Univariate predictors of ST segment depression included the coronary artery jeopardy score, the presence and the extent of reversible perfusion defects, the presence of three-vessel and/or left main coronary artery disease, and diastolic blood pressure at peak adenosine infusion. There was a trend (P = 0.06) to a higher incidence of collateral vessels in patients developing ST segment depression. The coronary artery jeopardy score was found to be the only significant independent predictor of ST segment depression by stepwise multivariate logistic regression analysis. Thus, in patients with angina pectoris, the coronary artery jeopardy score, representing the extent of significant coronary artery disease, is the most important independent predictor of adenosine-induced ST segment depression. ST depression is unusual in the absence of reversible perfusion defects and is also associated with more extensive reversible defects.

Adenosine↗
PubMed1993

De novo cisplatinum resistance does not influence cellular radiosensitivity.

The intrinsic sensitivity to 4 MeV photons, and 62.5 MeV (p-->Be+) neutrons has been examined in a panel of 11 cultured human cell lines exhibiting a wide spectrum of inherent cisplatinum sensitivity. Irrespective of whether cellular sensitivities to these therapeutic agents were compared at the 10% survival level, relative to the initial portion of the cell survival curves, or to their relative rank order of response, there were no significant correlations between inherent cisplatinum sensitivity and sensitivity to either 4 MeV photon, or 62.5 MeV neutron irradiation. This data raises the possibility that the previously reported decreased radiosensitivity of human tumour cell lines with acquired cisplatinum resistance may be due to the induction of cellular processes which confer resistance to both cisplatinum and ionising radiation, rather than the selection of innately cisplatinum-resistant cells, which are collaterally radioresistant.

Cell Line↗
PubMed2003

Moyamoya disease in a patient with schizophrenia.

We present the case of a 23-year-old Vietnamese male with a 2-year history of a psychotic illness marked by prominent negative symptoms, fatuousness and disturbed behavior. Neuroimaging revealed a prominent vascular flow void affecting the middle and anterior cerebral arteries, with associated increased collateral supply to the frontal cortex, consistent with Moyamoya disease. Neurological examination was unremarkable; however, neuropsychological assessment revealed significant executive dysfunction, including stimulus-driven behavior. Whilst the diagnosis of schizophrenia and Moyamoya disease may be coincidental, an interaction between the 2 diseases may have led to some of the atypical features of this case, including prominent executive dysfunction and marked sensitivity to psychotropic medication. We discuss the nature of possible interactions between the 2 conditions. This case also highlights the importance of re-evaluating patients with atypical or treatment-resistant psychoses for cerebral pathology.

Adult↗
PubMed1988

Frequency-dependent N-methyl-D-aspartate receptor-mediated synaptic transmission in rat hippocampus.

1. The effects of the N-methyl-D-aspartate (NMDA) antagonist, D-2-amino-5-phosphonovalerate (APV) were examined on synaptic responses evoked by high-frequency stimulation of the Schaffer collateral-commissural pathway, in the presence of Mg2+ (1 or 2 mM) and functional synaptic inhibition. 2. The synaptic response evoked by 100 Hz stimulation comprised fast excitatory postsynaptic potentials (EPSPs) evoked by each shock and a slow depolarization. APV reduced the size of the depolarization without depressing the fast EPSPs. 3. The mean (+/- 1 S.E.) amplitude of the APV-sensitive component (3.0 +/- 0.3 mV), evoked by 100 Hz stimulation at membrane potentials near rest, was invariably smaller than the first fast EPSP (9.8 +/- 0.7 mV). Both of these synaptic components had similar thresholds and increased in amplitude as the stimulus intensity was raised. There was a positive correlation between the amplitude of the two components (r = 0.57, P less than 0.01). 4. The amplitude of the APV-sensitive component was positively correlated (r = 0.97, P less than 0.05) with the frequency of stimulation during the trains (between 10 and 100 Hz). The threshold frequency for evoking an APV-sensitive component was approximately 10 Hz. 5. In contrast to the fast EPSPs the amplitude of the APV-sensitive component increased with depolarization, and decreased with hyperpolarization, of a neurone from its resting membrane potential. The component was no longer present in some cells which had been hyperpolarized sufficiently. 6. It is suggested that during high-frequency stimulation a neurone may become depolarized for a sufficient time to reduce the Mg2+ block of NMDA channels. This enables the NMDA receptor system to contribute transiently to the synaptic response, despite the inhibitory synaptic mechanisms which prevent its activation during single-shock stimulation. The characteristics of the NMDA receptor-mediated synaptic response may explain properties relating to the induction of long-term potentiation (LTP).

2-Amino-5-phosphonovalerate↗
PubMed1976

Baroreflex sensitivity and carotid sinus dimensions in dogs with coarctation.

Baroreflex sensitivity (BRS) has not been assessed in coarctation, though it is diminished in renal and essential hypertension. Previous experimental studies of coarctation have dealt primarily with renal mechanisms of hypertension, and have relied on constricting the aorta in adult animals. We banded the thoracic aorta in newborn puppies, and performed studies 2 yr later. Blood pressure (BP) elevations, abundant chest wall collaterals, the absence of heart failure, and subsequent necropsy confirmed the full syndrome of natural coarctation in all dogs. Transient BP elevations were induced in conscious, unrestrained dogs with intravenous phenylephrine injections. Reflex bradycardia was quantitated by plotting each pulse interval in microseconds against BP of the preceding beat, and expressing BRS as the linear regression coefficient (slope) in ms/mmHg. Mean BRS in 10 dogs with coarctation did not differ significantly (P greater than 0.1) from 8 normal controls. Carotid sinus diameter (CSD) was also assessed. Carotid arteries were fixed in vivo by prolonged exposure to glutaraldehyde to prevent contraction, then were excised and measured in a calibrated microscope. Mean CSD in 10 dogs with coarctation was significantly greater (P less than 0.01) than in 10 control dogs. The unexpectedly normal BRS in experimental coarctation may be due to changes in CSD induced by hypertension; such changes may only develop in growing animals. Experimental studies of coarctation should use a preparation that mimics the natural lesion.

Animals↗
PubMed1995

The value of portal vein pulsatility on duplex sonograms as a sign of portal hypertension in children with liver disease.

OBJECTIVE: The purpose of this study was to determine the significance of portal vein pulsatility on duplex Doppler waveforms in children with end-stage hepatic failure undergoing liver transplantation. SUBJECTS AND METHODS: Thirty-eight children with end-stage hepatic decompensation were examined with color-assisted spectral Doppler waveform analysis of the hepatic artery and the portal vein. Correlation was made with age, duration of illness, clinical and pathologic diagnosis, and presence of portal hypertension. Findings were compared with those for six patients with acute viral hepatitis and 12 healthy control subjects. RESULTS: Portal vein pulsatility was noted in all 36 patients in whom portal vein flow was detected by Doppler imaging. The majority of these (34) had clinical or sonographic evidence of portal hypertension. In two patients, no portal vein flow was identified in the liver hilum; both had a large portosystemic shunt through collaterals or surgical graft. Significantly increased pulsatility of the hepatic artery waveform (resistive index [RI] = 0.89 +/- 0.15, p < .0001) was seen in patients with end-stage liver disease. In contrast, no portal vein pulsatility and normal hepatic artery pulsatility (RI = 0.60 +/- 0.11) was noted in all patients with acute hepatitis and control subjects. CONCLUSION: Portal vein waveform pulsatility is 94% sensitive and 90% specific for portal hypertension in end-stage liver disease.

Acute Disease↗
PubMed1998

Congenital heart disease: measuring physiology with MRI.

Cine MRI and VEC MRI can be used to quantitate the physiology of the heart and great vessels in patients with CHD. This information can be a valuable adjunct to anatomical imaging for preoperative planning as well as postoperative monitoring. Some important clinical applications of quantitative cardiovascular functional MRI include measurement of ventricular masses, stroke volumes, and ejection fractions; estimation of shunts and valvular regurgitation; assessment of collateral blood flow and pressure gradients in aortic coarctation; and postsurgical evaluation of conduit blood flow and pressure gradients.

Cardiac Volume↗
PubMed2000

Angiogenesis: a "breakthrough" technology in cardiovascular medicine.

The identification of angiogenic growth factors has generated the opportunity for novel therapies in the treatment of a variety of diseases. Antibodies and/or naturally occurring angiogenesis inhibitors are being investigated clinically to antagonize key angiogenic factors. The strategy is designed to eliminate the vascular infrastructure and thereby minimize the extent of pathological consequences to the patient. A complementary strategy is likely to emerge for the treatment of cardiovascular diseases. Clinical trials of therapeutic angiogenesis have already been initiated in patients with myocardial ischemia and peripheral vascular disease. These include trials of recombinant protein therapy as well as gene transfer. While preliminary applications of gene therapy have established proof of the concept that angiogenic growth factors can augment collateral artery development in human subjects, many questions remain to be answered.

Angiogenesis Inducing Agents↗
PubMed1992

Value of endoscopic ultrasonography in the management of portal hypertension.

Using endoscopic ultrasonography (EUS) a large part of the portal venous system can be visualized. In 40 patients with portal hypertension (PH) and in 48 control subjects EUS displayed the azygos, splenic, mesenteric and portal veins in both groups. However, esophageal and gastric varices, peri- esophageal and peri-gastric collateral veins and submucosal gastric venules were displayed only in patients with PH. EUS was inferior to endoscopy for detecting and grading esophageal varices (p less than 0.0005), but superior in the detection of varices in the fundus of the stomach (p less than 0.0005). EUS cannot be considered a reliable method for the study of esophageal varices: it has an overall sensitivity of 50%, does not permit flow measurements, and does not provide information that could be used to estimate the risk of bleeding. EUS has been demonstrated to be superior to endoscopy in the diagnosis of gastric varices. This finding is extremely important for the optimal selection of treatment of patients with portal hypertension. EUS can detect portal hypertensive gastropathy; thus inflammatory gastritis can be more easily distinguished from congestive gastropathy and therapeutic decisions are strongly influenced.

Azygos Vein↗
PubMedDate not supplied

Comparison of the inhibitory effects of nifedipine, nitroglycerin, and nitroprusside sodium on different types of activation in canine coronary arteries, with comparative studies in human coronary arteries.

The mechanical activity of helical strips from canine coronary arteries was recorded. Vessels from normal hearts and from hearts with a collateral circulation after experimental occlusion were investigated. Two types of activation were studied: (a) activation induced by noradrenaline, 10(-5) M, after blockade of beta-adrenoceptors with propranolol (NA activation) and (b) activation induced by application of tetraethylammonium (TEA), 10(-2) M, after blockade of endogenous prostaglandin synthesis by indomethacin, 2 X 10(-6) M (TEA activation). TEA activation was more sensitive to nifedipine (ED50, 2 X 10(-8) M) than to nitroglycerin (ED50, 10(-7) M) or nitroprusside sodium (ED50, 3 X 10(-7) M). NA activation, on the other hand, was more sensitive to nitroglycerin (ED50, 10(-8) M) or nitroprusside sodium (ED50, 2 X 10(-8) M) than to nifedipine (ED50, 6 X 10(-8) M). In comparative studies with human coronary arteries excised postmortem, spontaneous rhythmic activity was often observed. This phasic activity was, as in TEA activation of canine coronary arteries, more sensitive to fedipine than to nitroglycerin. The differences between human and canine coronary smooth muscle are discussed.

Animals↗
PubMed2001

A broad diagnostic battery for bedside transcranial Doppler to detect flow changes with internal carotid artery stenosis or occlusion.

BACKGROUND AND PURPOSE: The authors establish accuracy parameters of a broad diagnostic battery for bedside transcranial Doppler (TCD) to detect flow changes due to internal carotid artery (ICA) stenosis or occlusion. METHODS: The authors prospectively studied consecutive patients with stroke or transient ischemic attack referred for TCD. TCD was performed and interpreted at bedside using a standard insonation protocol. A broad diagnostic battery included major criteria: collateral flow signals, abnormal siphon or terminal carotid signals, and delayed systolic flow acceleration in the middle cerebral artery. Minor criteria included a unilateral decrease in pulsatility index (< or = 0.6 or < or = 70% of contralateral side), flow diversion signs, and compensatory velocity increase. Angiography or carotid duplex ultrasound (CDU) was used to grade the degree of carotid stenosis using North American criteria. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of TCD findings were determined. RESULTS: Seven hundred and twenty patients underwent TCD, of whom 517 (256 men and 261 women) had angiography and/or CDU within 8.8 +/- 0.9 days. Age was 63.1 +/- 15.7 years. For a 70% to 99% carotid stenosis or occlusion, TCD had sensitivity of 79.4%, specificity of 86.2%, PPV of 57.0%, NPV of 94.8%, and accuracy of 84.7%. For a 50% to 99% carotid stenosis or occlusion, TCD had sensitivity of 67.5%, specificity of 83.9%, PPV of 54.5%, NPV of 90.0%, and accuracy of 81.6%. TCD detected intracranial carotid lesions with 84.9% accuracy and extracranial carotid lesions with 84.4% accuracy (sensitivity of 88% and 79%, specificity of 85% and 86%, PPV of 24% and 54%, and NPV of 99% and 95%, respectively). The prevalence of the ophthalmic artery flow reversal was 36.4% in patients with > or = 70% stenosis or occlusion. If present, this finding indicated a proximal ICA lesion location in 97% of these patients. CONCLUSIONS: In symptomatic patients, bedside TCD can accurately detect flow changes consistent with hemodynamically significant ICA obstruction; however, TCD should not be a substitute for direct carotid evaluation. Because TCD is sensitive and specific for a > or = 70% carotid stenosis or occlusion in both extracranial and intracranial carotid segments, it can be used as a complementary test to refine other imaging findings and detect tandem lesions.

Angiography↗
PubMed2002

Development of allogeneic hematopoietic stem cell transplantation (HSCT).

The field of BMT has entered a new phase based on insights into basic molecular and cellular biology. The mechanism of cure mediated by allogeneic HSCT is now believed to be at least partially mediated by cellular attack against tumor-associated antigens. Better understanding of these cellular targets and the means of targeting them specifically will allow a more precise application of cellular therapy than is currently possible. This in turn may make it possible to design therapies that are increasingly selective without the collateral toxicities of GVHD, infection, and direct organ damage that currently are the limiting features of allogeneic HSCT as practiced until recently. However, it remains a challenge to demonstrate that disease-control using reduced intensity preparative regimens is at least comparable to that achieved by traditional myeloablative HSCT. This will require carefully controlled studies in each the major diseases that have shown sensitivity to the immune-mediated effects of HSCT. The chapters below will highlight progress towards the goals of elucidating the role of NST.

Animals↗
PubMedDate not supplied

Laparoscopic intracorporeal bowel resection with ultrasound versus electrosurgical dissection.

BACKGROUND AND OBJECTIVES: We assessed resection time and collateral thermal tissue damage of ultrasonically activated surgery (UAS) and high-frequency blade-enhanced bipolar electrosurgery (BE) in laparoscopic bowel surgery. METHODS: We compared UAS laparoscopic intracorporeal small bowel mesentery re-section with an equivalent procedure performed with BE in a porcine model. Resection was defined as 12 end-arcade arteries supplying the intended bowel segment. Vessels were divided one cm off the bowel wall. Aside from shaft diameter, jaws gaping pattern, and cutting blade length, UAS and BE devices were well matched for handle ergonomics, jaws gaping extent, power setting, type of use, working shaft axial rotation, and length. A pathologist blind to the method used assessed the collateral thermal damage. Resections were allocated to either method by computer-generated block randomization. The study design was sequential triangular with a 5% significance level and 90% power. RESULTS: No significant differences occurred in intraoperative blood pressure and heart rate variations in pigs undergoing UAS or BE. Median operating time (measured after 10, 20, and 30 resections in each study arm) was significantly shorter in UAS than in BS (0.57 vs. 2.01 min P < 0.001). Histology of small bowel wall specimens revealed no collateral thermal damage. CONCLUSIONS: UAS laparoscopic bowel surgery offers reduced resection time as com-pared with its BE counterpart in a porcine model.

Animals↗
PubMed2001

Exercise training in coronary artery disease and coronary vasomotion.

Exercise training has assumed a major role in cardiac rehabilitation, mostly because of its positive effects on myocardial perfusion in patients with coronary artery disease. The mechanisms involved in mediating this key effect have long been debated: both regression of coronary artery stenosis and improvement of collateralization have been suggested as potential adaptations. However, the comparatively minute changes in luminal diameter and myocardial contrast staining do not fully explain the significant changes in myocardial perfusion. During the last decade, endothelial dysfunction was identified as a trigger of myocardial ischemia. The impaired production of endothelium-derived nitric oxide (NO) in response to acetylcholine and flow leads to paradoxic vasoconstriction and exercise-induced ischemia. Recently, it was confirmed in humans that training attenuates paradoxic vasoconstriction in coronary artery disease and increases coronary blood flow in response to acetylcholine. Data from cell-culture and animal experiments suggest that shear stress acts as a stimulus for the endothelium to increase the transport capacity for L-arginine (the precursor molecule for NO), to enhance NO synthase activity and expression, and to increase the production of extracellular superoxide dismutase, which prevents premature breakdown of NO. Exercise also affects the microcirculation, where it sensitizes resistance arteries for the vasodilatory effects of adenosine. These novel findings provide a pathophysiological framework to explain the improvement of myocardial perfusion in the absence of changes in baseline coronary artery diameter. Because endothelial dysfunction has been identified as a predictor of coronary events, exercise may contribute to the long-term reduction of cardiovascular morbidity and mortality.

Animals↗