Reassessing the Carotid Artery Plaque "Rim Sign" on CTA: A New Analysis with Histopathologic Confirmation.

BACKGROUND AND PURPOSE: The CTA "rim sign" has been proposed as an imaging marker of intraplaque hemorrhage in carotid plaques. This study sought to investigate such findings using histopathologic confirmation. MATERIALS AND METHODS: Included patients had CTA neck imaging <1 year before carotid endarterectomy. On imaging, luminal stenosis and the presence of adventitial (<2-mm peripheral) and "bulky" (≥2-mm) calcifications, total plaque thickness, soft-tissue plaque thickness, calcification thickness, and the presence of ulcerations were assessed. The rim sign was defined as the presence of adventitial calcifications with internal soft-tissue plaque of ≥2 mm in maximum thickness. Carotid endarterectomy specimens were assessed for both the presence and the proportional makeup of lipid material, intraplaque hemorrhage, and calcification. RESULTS: Sixty-seven patients were included. Twenty-three (34.3%) were women; the average age was 70.4 years. Thirty-eight (57.7%) plaques had a rim sign on imaging, with strong interobserver agreement (κ = 0.85). A lipid core was present in 64 (95.5%) plaques (average, 22.2% proportion of plaque composition); intraplaque hemorrhage was present in 52 (77.6%), making up, on average, 13.7% of the plaque composition. The rim sign was not associated with the presence of intraplaque hemorrhage (P = .11); however, it was associated with a greater proportion of intraplaque hemorrhage in a plaque (P = .049). The sensitivity and specificity of the rim sign for intraplaque hemorrhage were 61.5% and 60.0%, respectively. CONCLUSIONS: The rim sign is not associated with the presence of intraplaque hemorrhage on histology. However, it is associated with a higher proportion of hemorrhage within a plaque and therefore may be a biomarker of more severe intraplaque hemorrhage, if present.

Why Not Dipyridamole: a Review of Current Guidelines and Re-evaluation of Utility in the Modern Era.

Dipyridamole is an old anti-platelet and coronary vasodilator agent that inhibits platelet phosphodiesterase and increases interstitial adenosine levels. Its use in coronary artery disease (CAD) has fallen out of practice in the modern era with the advent of new anti-platelet agents, and most modern guidelines on the management of CAD either neglect to comment on its utility or outright recommend against it. The majority of the studies used in these guidelines are outdated and took place in an era when high doses of aspirin were used and statins were not widely utilized. There is growing evidence in rat models of dipyridamole's synergy with statins through adenosine modulation resulting in significant myocardial protection against ischemia-reperfusion injury and limitation of infract size. The data in human studies are limited but show a similar potential synergy between dipyridamole and statins. It would thus be prudent to reconsider the recommendations against the use of dipyridamole in CAD and to re-evaluate its possible role and potential benefits through well-designed randomized trials combining it with statins, low-dose aspirin, and/or other anti-platelet agents.

A Metabolic Intravascular Platform to Study FDG Uptake in Vascular Injury.

PURPOSE: Metabolic alterations underlie many pathophysiological conditions, and their understanding is critical for the development of novel therapies. Although the assessment of metabolic changes in vivo has been historically challenging, recent developments in molecular imaging have allowed us to study novel metabolic research concepts directly in the living subject, bringing us closer to patients. However, in many instances, there is need for sensors that are in close proximity to the organ under investigation, for example to study vascular metabolism. METHODS: In this study, we developed and validated a metabolic detection platform directly in the living subject under an inflammatory condition. The signal collected by a scintillating fiber is amplified using a photomultiplier tube and decodified by an in-house tunable analysis platform. For in vivo testing, we based our experiments on the metabolic characteristics of macrophages, cells closely linked to inflammation and avid for glucose and its analog 18F-fluorodeoxyglucose (18F-FDG). The sensor was validated in New Zealand rabbits, in which inflammation was induced by either a) high cholesterol (HC) diet for 16 weeks or b) vascular balloon endothelial denudation followed by HC diet. RESULTS: There was no difference in weight, hemodynamics, blood pressure, or heart rate between the groups. Vascular inflammation was detected by the metabolic sensor (Inflammation: 0.60 ± 0.03 AU vs. control: 0.48 ± 0.03 AU, p = 0.01), even though no significant inflammation/atherosclerosis was detected by intravascular ultrasound, underscoring the high sensitivity of the system. These findings were confirmed by the presence of macrophages on ex vivo aortic tissue staining. CONCLUSION: In this study, we validated a tunable very sensitive metabolic sensor platform that can be used for the detection of vascular metabolism, such as inflammation. This sensor can be used not only for the detection of macrophage activity but, with alternative probes, it could allow the detection of other pathophysiological processes.

Micro-RNAS Regulate Metabolic Syndrome-induced Senescence in Porcine Adipose Tissue-derived Mesenchymal Stem Cells through the P16/MAPK Pathway.

Mesenchymal stem cells (MSCs) constitute an important repair system, but may be impaired by exposure to cardiovascular risk factors. Consequently, adipose tissue-derived MSCs from pigs with the metabolic syndrome (MetS) show decreased vitality. A growing number of microRNAs (miRNAs) are recognized as key modulators of senescence, but their role in regulating senescence in MSC in MetS is unclear. We tested the hypothesis that MetS upregulates in MSC expression of miRNAs that can serve as post-transcriptional regulators of senescence-associated (SA) genes. MSCs were collected from swine abdominal adipose tissue after 16 weeks of Lean or Obese diet ( n = 6 each). Next-generation miRNA sequencing (miRNA-seq) was performed to identify miRNAs up-or down-regulated in MetS-MSCs compared with Lean-MSCs. Functional pathways of SA genes targeted by miRNAs were analyzed using gene ontology. MSC senescence was evaluated by p16 and p21 immunoreactivity, H2AX protein expression, and SA-ß-Galactosidase activity. In addition, gene expression of p16, p21, MAPK3 (ERK1) and MAPK14, and MSC migration were studied after inhibition of SA-miR-27b. Senescence biomarkers were significantly elevated in MetS-MSCs. We found seven upregulated miRNAs, including miR-27b, and three downregulated miRNAs in MetS-MSCs, which regulate 35 SA genes, particularly MAPK signaling. Inhibition of miR-27b in cultured MSCs downregulated p16 and MARP3 genes, and increased MSC migration. MetS modulates MSC expression of SA-miRNAs that may regulate their senescence, and the p16 pathway seems to play an important role in MetS-induced MSC senescence.

Effect of Low-Dose Rapamycin on Senescence Markers and Physical Functioning in Older Adults with Coronary Artery Disease: Results of a Pilot Study.

Rapamycin, an mTOR inhibitor affects senescence through suppression of senescence-associated secretory phenotype (SASP). We studied the safety and feasibility of low-dose rapamycin and its effect on SASP and frailty in elderly undergoing cardiac rehabilitation (CR). 13 patients; 6 (0.5mg), 6 (1.0mg), and 1 patient received 2mg oral rapamycin (serum rapamycin <6ng/ml) daily for 12 weeks. Median age was 73.9±7.5 years and 12 were men. Serum interleukin-6 decreased (2.6 vs 4.4 pg/ml) and MMP-3 (26 vs 23.5 ng/ml) increased. Adipose tissue expression of mRNAs (arbitrary units) for MCP-1 (3585 vs 2020, p=0.06), PPAR-γ (1257 vs 1166), PAI-1 (823 vs 338, p=0.08) increased, whereas interleukin-8 (163 vs 312), TNF-α (75 vs 94) and p16 (129 vs 169) decreased. Cellular senescence-associated beta galactosidase activity (2.2% vs 3.6%, p=0.18) tended to decrease. We observed some correlation between some senescence markers and physical performance but no improvement in frailty with rapamycin was noted. (NCT01649960).

Fotogrametría del perfil facial en ortodoncia / Photogrammetry of facial profile in orthodontics

Se incorporaron dos sencillos elementos en las fotografías del perfil facial en ortodoncia. La aplicación de un sello, automático, de tinta común con una escala preestablecida de aplicación fácil, ágil y reproducible, directamente sobre la piel del paciente, para otorgar mayorprecisión en la comparación de imágenes en el tiempo; como así también, la utilización de un plano de referencia denominado plano lefraconformado por dos puntos que unen ojo y oído, permitiendo evaluar los cambios producidos en el rostro por medio de la superposición fotográfica. Al finalizar el presente trabajo se concluyo que la utilización del sello y la superposición sobre el plano lefra permiten asimilar eltamaño de las fotografías y a su vez dar una zona referencial estable, facilitando la comparación entre el pre y post tratamiento.

Two simple elements were incorporated in the photographs of facial profile in orthodontics. The application of a seal, automatic, common ink on a prescribed scale of easy, fast and reproducible application, directly on the skin of the patient profile, which gives more accurate comparison of images in time; as well as the use of a reference plane called lefra plane, which consists of two points linking eye and ear, allowing to evaluate the changes in the face by means of photographic superimposition. Upon completion of this work, was concluded that the use of the seal and the overlay on the lefra plane allow to assimilate the size of the photographs and in turn provide a stable reference area to facilitate the comparison between pre and post treatment.

Beneficial effects of polyphenol-rich olive oil in patients with early atherosclerosis.

PURPOSE: Diets rich in plant-derived polyphenols such as olive oil (OO) and/or catechins such as epigallocatechin 3-gallate (EGCG) have been shown to reduce the incidence of cardiovascular diseases, potentially by improving endothelial function, an important surrogate for atherosclerosis. The possible augmentation of endothelial function with the combined efforts of OO and EGCG is intriguing, yet unknown. METHODS: Eighty-two patients with early atherosclerosis (presence of endothelial dysfunction) were enrolled in this double-blind, randomized trial with 52 completing the study. The aim of the study was to compare the effect of a daily intake of 30 ml simple OO, with 30 ml of EGCG-supplemented OO, on endothelial function as well as on inflammation and oxidative stress after a period of 4 months. Endothelial function was assessed noninvasively via peripheral arterial tonometry (Endo-PAT®). RESULTS: After 4 months, when OO and EGCG-supplemented OO groups were combined, OO significantly improved endothelial function (RHI, 1.59 ± 0.25-1.75 ± 0.45; p < 0.05). However, there were no significant differences in results between the two olive oil groups. Interestingly, with OO supplementation there was a significant reduction in inflammatory parameters: sICAM (196 to 183 ng/mL, p = < 0.001); white blood cells (WBCs) (6.0 × 109/L-5.8 × 109/L, p < 0.05); monocytes (0.48 × 109/L to 0.44 × 109/L, p = 0.05); lymphocytes (1.85 × 109/L to 1.6 × 109/L, p = 0.01); and platelets (242-229 × 109/L, p = 0.047). CONCLUSIONS: Improvement in endothelial dysfunction in patients with early atherosclerosis in association with significant reduction in leukocytes may suggest an important role of early cellular inflammatory mediators on endothelial function. The current study supports one potential mechanism for the role of olive oil, independent of EGCG, modestly supplemented to a healthy cardiovascular diet.

Role of oxidative stress in hypoxia preconditioning of cells transplanted to the myocardium: a molecular imaging study.

AIM: Cell-based therapies are a potential therapeutic alternative for the treatment of coronary artery disease (CAD). However, transplanted cells undergo significant death in the living subject. Hypoxic preconditioning (HPC) is a potential intervention to increase transplanted cell survival. However, the biological mechanisms of this benefit remain unclear. We hypothesize that the beneficial effect of HPC on stem cell survival is in part due to preservation of oxidant status, an effect that will be monitored using state-of-the-art molecular imaging. METHODS: H9c2 rat cardiomyoblasts expressing the construct CMV-firefly luciferase (h9c2-fluc), with and without HPC, were exposed to hypoxia, and oxidative stress and cell survival were measured. Subsequently, H9c2-fluc cells, with and without HPC, were injected into the myocardium of rats and cell survival was monitored daily with Bioluminescence (BLI) using a CCD camera. RESULTS: Compared to controls, cells exposed to hypoxia had increased amount of reactive oxygen species (ROS, control: 14.1±0.9 vs. hypoxia: 19.5 ± 2.0 RFU/µg protein, P=0.02) and decreased cell survival (control: 0.29 ± 0.005 vs. hypoxia: 0.24 ± 0.005 OD, P<0.001). HPC treatment decreased the amount of hypoxia-induced ROS (HPC: 11.5 ± 0.7RFU/µg protein, P=0.002 vs. hypoxia and P=0.11 vs. control), associated with improved survival (HPC: 0.27 ± 0.004OD/µg protein, P=0.002 vs. hypoxia and P=0.005 vs. control). Most importantly, compared to un-conditioned cells, HPC-cells had increased cell survival after transplantation to the myocardium (C: 34.7 ± 6.7% vs. HPC: 83.4 ± 17.5% at day 5 compared to day 1, P=0.01). CONCLUSION: The beneficial effect of HPC is in part due to preservation of oxidant status. Molecular imaging can assess changes in cell survival in the living subject and has the potential to be applied clinically.

The importance of reendothelialization after arterial injury.

Atherosclerosis is still the principal cause of morbidity and mortality in Western countries and although a significant progress has been made in the understanding of its pathophysiology, the determinants of atherosclerotic plaque instability are still poorly understood. The endothelium plays a pivotal role for the development, progression, and complication of atherosclerosis. Endothelial dysfunction is widely recognized as one of the early alteration in the vessel wall preceding the development of the plaque. However, considering the plethora of vascular functions which are regulated by endothelium, it plays a pivotal role throughout the atherosclerotic process and indeed the loss of endothelial cells, leading to plaque denudation, is one of the main causes of plaque complication. It is therefore conceivable that the maintenance of the endothelial layer physical continuity and function is crucial for the prevention of atherosclerosis. In the presence of cardiovascular risk factors, endothelial cells are continuously injured and repaired by the proliferation of resident cells and circulating endothelial progenitor cells. Indeed the number of circulating endothelial progenitor cells has been identified as an predictor of cardiovascular events. The increase in bone marrow release of endogenous progenitor cells or the enhancement of their homing in arterial denuded sites or in intravascular stent surface, are currently pursued to reduce atherosclerosis development/complication and intrastent restenosis, respectively. However, some challenges may arise from procedures enhancing endothelialization, including unwanted angiogenesis which may favor neoplasia progression and paradoxically atherosclerotic plaque expansion and complication.

Mild renal insufficiency is associated with reduced coronary flow in patients with non-obstructive coronary artery disease.

Patients with chronic kidney disease (CKD) have increased risk for cardiovascular events. However, the association between these pathophysiological processes is unclear. Therefore, this study was designed to determine the association between early CKD and coronary microvascular disease in patients with normal or mildly diseased coronary arteries. A total of 605 patients with normal or mildly diseased coronary arteries based on angiography underwent coronary flow reserve (CFR) evaluation using intracoronary adenosine. Patients were divided based on glomerular filtration rate (GFR). CKD was defined as calculated GFR<60 ml/min/1.73 m(2). Patients with normal GFR (> or =60 ml/min/1.73 m(2), n=481) had higher CFR compared to those with CKD (n=124, CFR=3.0+/-0.8 vs 2.6+/-0.6, P<0.001, respectively). Patients with abnormal GFR were more likely to be older and of female gender, with greater prevalence of hypertension. Multiple logistic regression analysis adjusted for the aforementioned risk factors further supported the observed relationship. The current study shows that reduced renal function is associated with attenuated coronary vasodilator capacity in patients without obstructive coronary artery disease. The correlation between low GFR and reduced CFR may suggest parallel alterations in the renal and coronary microcirculation at the early stage of disease. Impairment in both microcirculatory beds may reflect an unmeasured risk factor induced by blunted renal function and add a burden to the increased propensity for cardiovascular events in CKD.

Coronary microvascular functional reserve: quantification of long-term changes with electron-beam CT preliminary results in a porcine model.

PURPOSE: To evaluate the ability of electron-beam computed tomography (CT) to help quantify long-term changes in coronary microvascular functional reserve in a porcine model. MATERIALS AND METHODS: Electron-beam CT-based intramyocardial blood volume and perfusion and Doppler ultrasonography (US)-based intracoronary blood flow were obtained in 13 pigs at baseline and again 3 months later. Measurements were obtained at rest and after the administration of adenosine. The short-term variation during 30 minutes of electron-beam CT measurements was assessed in nine additional pigs. RESULTS: Short-term variation of blood volume and perfusion averaged 8% and 9%, respectively, and was similar for both weight groups at rest and after adenosine administration. At rest, intracoronary blood flow, blood volume, and perfusion remained unchanged from baseline to follow-up. Long-term increases (percentage change with adenosine relative to that at rest) in blood volume and perfusion reserves were consistent with increasing intracoronary blood flow reserves. Despite these long-term changes in intracoronary blood flow, blood volume, and perfusion, the blood volume-to-perfusion relationship suggests a similar blood volume distribution among different microvascular functional components in normal porcine myocardium at both weight groups. CONCLUSION: Electron-beam CT may be of value for quantifying long-term changes in intramyocardial microvascular function.

Incremental doses of intracoronary adenosine for the assessment of coronary velocity reserve for clinical decision making.

Achievement of maximal vasodilatation of the coronary microcirculation is a prerequisite for the measurement of coronary flow reserve (CFR). The present study was designed to address the hypothesis that intracoronary adenosine yields more complete vasodilation of the coronary microcirculation when incremental doses are used, resulting in higher and more accurate coronary flow reserve measurements. Four hundred and fifty-seven patients were divided in two groups; group I (319 patients) comprised patients without angiographic evidence of significant coronary artery disease, while group II (138 patients) comprised patients with intermediate coronary stenoses (between 40% and 70% diameter stenosis). Coronary velocity reserve (CVR, a surrogate measurement for CFR) was measured during cardiac catheterization using a Doppler-tipped guidewire. Incremental doses of intracoronary adenosine (12 to 54 microg for the left coronary artery and 6 to 42 microg for the right coronary artery) were administered. There was a significant difference between the initial dose of adenosine and the subsequent incremental doses. Of a total of 479 observations, only 192 (40%) had the maximal CVR value at the first dose. Thirty-nine percent of the patients in group I and 27% in group II with an initial CVR value < 2.5 increased CVR to > or = 2.5 with incremental doses of adenosine. This study suggests that incremental doses of adenosine should be used to achieve maximal CVR for the assessment of the functional significance of coronary lesions. Cathet Cardiovasc Intervent 2001;54:34-40.

The effect of endothelin-1 on nuclear factor kappa B in macrophages.

Nuclear factor kappaB (NF-kappaB) is a transcriptional factor which may be pivotal in the pathogenesis of atherosclerosis. Endothelin-1 (ET-1) is a peptide with proatherogenic properties. We hypothesized that ET-1 may act through activation of NF-kappaB and degradation of IkappaB-alpha, the cytosolic inhibitor of NF-kappaB activation, to create an atherogenic environment. The human monocytic cell line THP-1 was stimulated with ET-1 +/- the ET antagonist, BQ788 and the proteosome inhibitor, PSI. LPS was used as a positive control. Gel shift assays for NF-kappaB activity and Western blot analysis for IkappaB-alpha were performed. Both LPS and ET-1 led to activation of NF-kappaB in nuclear extracts [3.4 +/- 0.45 (LPS) and 2.9 +/- 0.26 (ET-1) fold increase in Arbitrary Densitometric Units (ADU) compared with negative control (P < 0.005 in both cases)]. In the presence of the ETB antagonist, BQ788, NF-kappaB activation was attenuated and not different from control (1.7 +/- 0.24 fold DU compared with negative control; P = NS). In addition, both LPS and ET-1 mediated NF-kappaB activation were attenuated by preincubation with the proteosome inhibitor, PSI (1.3 +/- 0.58 and 1.1 +/- 0.3 fold increase in ADU compared with negative control respectively). Both LPS and ET-1 led to a decrease in the amount of IkappaB-alpha present in the THP-1 cytoplasmic extracts (2.1 +/- 1.5% and 54 +/- 15.7% of ADU vs negative control (P < 0.05). NF-kappaB is activated by ET-1 in human THP-1 monocytes. This data supports a role for the ETs in the development of inflammation in the vessel wall in atherosclerosis.

Obesity is independently associated with coronary endothelial dysfunction in patients with normal or mildly diseased coronary arteries.

OBJECTIVES: This study evaluates the impact of obesity on coronary endothelial function in patients with normal or mild coronary artery disease. BACKGROUND: The American Heart Association (AHA) has recently classified obesity as a modifiable risk factor for coronary heart disease. METHODS: A total of 397 consecutive patients with normal or mildly diseased coronary arteries at angiography underwent coronary vascular reactivity evaluation using intracoronary adenosine, acetylcholine and nitroglycerin. Patients were divided into three groups based on the body mass index (BMI): Group 1, patients with a BMI <25 (n = 117, normal weight); Group 2, patients with a BMI 25-30 (n = 149, overweight) and Group 3, patients with a BMI >30 (n = 131, obese). RESULTS: There were no significant differences among the groups in regard to other cardiovascular risk factors, except that overweight but not obese patients were significantly older than normal-weight patients (47 +/- 1 years in Group 1, 53 +/- 1 years in Group 2 and 50 +/- 1 years in Group 3, p < 0.001). The percent change of coronary blood flow to acetylcholine (%delta CBF Ach) was significantly lower in the obese patients than in the normal-weight group (85.2 +/- 12.0% in Group 1, 63.7 +/- 10.0% in Group 2 and 38.1 +/- 9.6% in Group 3, p = 0.009). By multivariate analysis, overweight (odds ratio, 1.55; 95% confidence interval, 1.2-2.0) and obesity (odds ratio, 2.41; 95% confidence interval, 1.5-4.0) status were independently associated with impaired coronary endothelial function. CONCLUSIONS: The study demonstrates that obesity is independently associated with coronary endothelial dysfunction in patients with normal or mildly diseased coronary arteries.

c-myc activation in early coronary lesions in experimental hypercholesterolemia.

This study tested the hypothesis that c-Myc activation, an oxidation-sensitive transcription factor, and its binding partner Max occurs in coronary arteries of hypercholesterolemic (HC) pigs, and can be attenuated by chronic antioxidant intervention. Coronary arteries were isolated from normal, HC pigs, or HC supplemented with antioxidant vitamins (HC + vitamins). The expression of the c-Myc/Max complex, and its target genes GADD45 and p53, was studied in nonatherosclerotic, early lesions (LL), positively staining for oil-red-O, in adjacent lesion-prone regions (PL), and in healthy segments (HV). The expression of c-Myc and Max in HC was 2- to 3-fold greater in PL, and 4-fold in LL, compared to normal vessels (P < 0.01). The expression of GADD45 was down-regulated, and of p53 increased, in the same regions. These alterations were attenuated in the HC + vitamins. Thus, c-Myc activation is an early atherosclerosis, in both PL and LL coronary arterial regions, and can be blunted by chronic dietary antioxidant intervention.

Altered effects of potassium channel modulation in the coronary circulation in experimental hypercholesterolemia.

OBJECTIVE: To evaluate the role of potassium channels in the regulation of coronary hemodynamics in experimental hypercholesterolemia. BACKGROUND: Potassium (K(+)) channels play an important role in coronary vasoregulation. It has previously been demonstrated that experimental hypercholesterolemia is associated with altered coronary vasomotion; however, the role of K(+) channels in modulating coronary blood flow in this pathophysiologic state has not been evaluated. METHODS AND RESULTS: Pinacidil (group 1, n=5) at 2 microg/kg per min, glibenclamide (group 2, n=5), or N-monomethyl-L-arginine (LNMMA) (group 3, n=4) at 50 microg/kg per min were infused into the left anterior descending artery of pigs prior to and following 10 weeks of 2% cholesterol diet. After 10 weeks of cholesterol feeding, intracoronary pinacidil resulted in a significant increase in coronary blood flow (CBF) and coronary artery diameter (CAD) compared to the normolipidemic state (111+/-10 versus 59+/-12%, and 6+/-1.1 versus 2.7+/-1.0%, respectively, P<0.05 for both comparisons), whereas intracoronary glibenclamide resulted in a significant decrease in CBF and CAD compared to the normolipidemic state (-17+/-5 versus 5+/-6%, and -0.8+/-1.4 versus 3.6+/-1.6%, respectively, P<0.05 for both comparisons). The effect of intracoronary LNMMA on CBF and CAD was significantly attenuated after 10 weeks of cholesterol feeding as compared to the normolipidemic state (-47+/-5.4 versus -0.8+/-6.8%, and -19.4+/-5.7 versus -2.3+/-3.3%, respectively, P<0.05 for both comparisons). Furthermore, pretreatment with intracoronary LNMMA did not alter the CBF response to pinacidil in normal pigs (group 4, n=4) (57.4+/-19 versus 59+/-12%, P=NS). CONCLUSIONS: The current study demonstrates an enhanced effect of coronary K(+) channel modulation and confirms the attenuated basal NO activity previously reported in experimental hypercholesterolemia. Acute withdrawal of basal NO activity alone, however, does not explain the enhanced effect of coronary K(+) channel modulation. These findings underscore the importance of the K(+) channel pathway in the regulation of coronary vasomotor tone in pathophysiologic states.

Hypercholesterolemia impairs myocardial perfusion and permeability: role of oxidative stress and endogenous scavenging activity.

OBJECTIVES: We intended to study the effect of hypercholesterolemia (HC) on myocardial perfusion and permeability response to increased cardiac demand. BACKGROUND: Hypercholesterolemia is associated with increased incidence of cardiac events and characterized by impaired coronary vascular function, possibly mediated partly through increased pro-oxidative conditions in plasma and tissue. However, it is yet unclear whether HC is also associated with impaired myocardial perfusion and vascular permeability responses in vivo. METHODS: For 12 weeks pigs were fed a normal, HC or HC diet supplemented daily with antioxidants (HC + AO, 100 IU/kg vitamin E and 1 g vitamin C). Myocardial perfusion and vascular permeability were measured in vivo using electron beam computed tomography before and after cardiac challenge with intravenous adenosine. Plasma and tissue oxidative status was determined ex vivo. RESULTS: Plasma cholesterol increased in all cholesterol-fed pigs but was associated with increased markers of oxidative stress only in HC pigs. Myocardial perfusion increased in response to adenosine in normal and HC + AO (+37 +/- 13% and +58 +/- 22%, respectively, p < 0.05 vs. baseline) but not in HC, whereas vascular permeability index increased only in HC pigs (+ 92 +/- 25%, p = 0.002). In HC animals, tissue endogenous oxygen radical scavengers and antioxidant vitamins were depleted and LDL oxidizability enhanced, but both were normalized in HC + AO pigs. Myocardial perfusion response was directly, and permeability inversely, associated with plasma and tissue vitamin concentrations. CONCLUSIONS: This study demonstrates that experimental HC is associated with blunted myocardial perfusion and increased vascular permeability responses in vivo to increased cardiac demand, which may be partly mediated by a shift in oxidative status.

Minimally invasive evaluation of coronary microvascular function by electron beam computed tomography.

BACKGROUND: We previously demonstrated that in vivo electron-beam computed tomography (EBCT)-based indicator-dilution methods provide an estimate of intramyocardial blood volume (BV) and perfusion (F), which relate as BV=aF+b radicalF, where a characterizes the recruitable (exchange) and b the nonrecruitable (conduit) component of the myocardial microcirculation. In the present study, we compared BV and F with intracoronary Doppler ultrasound-based coronary blood flow (CBF) as a method for detecting and quantifying differential responses of these microvascular components to vasoactive drugs in normal (control) and hypercholesterolemic (HC) pigs. METHODS AND RESULTS: BV and F values were obtained from contrast-enhanced EBCT studies in 14 HC and 14 control pigs. BV, F, and CBF values were obtained at baseline (intracoronary infusion of saline) and after 5 minutes each of intracoronary infusion of adenosine (100 microgram. kg(-1). min(-1)) and nitroglycerin (40 microgram/min). BV and CBF reserves in response to adenosine were attenuated in HC pigs compared with controls (90+/-36% versus 127+/-42%, P<0.03, and 485+/-182% versus 688+/-160%, P<0.01, respectively). The relationship between BV and F showed consistently lower recruitable BV in HC versus control pigs. Nonrecruitable BV reserve in response to adenosine was attenuated in HC compared with controls (77+/-20% versus 135+/-28%, P<0.001). Our findings are consistent with HC-induced impairment of intramyocardial resistance vessel function. CONCLUSIONS: EBCT technology allows minimally invasive evaluation of intramyocardial microcirculatory function and permits assessment of microvascular BV distribution in different functional components. This method may be of value in evaluating the coronary microcirculation in pathophysiological states such as hypercholesterolemia.

Attenuated coronary flow reserve and vascular remodeling in patients with hypertension and left ventricular hypertrophy.

OBJECTIVES: The purpose of this study was to evaluate the association between hypertension and left ventricular hypertrophy (LVH) with both coronary vascular remodeling and endothelial function. BACKGROUND: The association between endothelial and nonendothelial coronary flow reserve with vascular remodeling in patients with hypertension and LVH is still unclear. METHODS: One hundred and eleven patients with normal or mildly diseased coronary arteries at angiography underwent intravascular ultrasound examination of the left anterior descending coronary artery. Patients were divided into three groups: group 1: n = 13, hypertensive patients with LVH; group 2: n = 30, hypertensive patients without LVH; group 3: n = 68, normotensive patients. Vessel and lumen area and atherosclerotic plaque area were evaluated. Vascular reactivity was examined using intracoronary adenosine and acetylcholine. RESULTS: Vessel area in group 1 (with LVH) was significantly (p < 0.01) greater than that in group 2 (without LVH), whereas, vessel area in both groups 1 and 3 was similar (12.8 +/- 0.8 mm2, 10.7 +/- 0.4 mm2 and 11.5 +/- 0.3 mm2). Coronary blood flow at baseline for patients in group 1 (with LVH) was significantly greater than it was for patients in groups 2 and 3 (81.1 +/- 9.9 ml/min, 56.5 +/- 6.2 ml/min and 48.1 +/- 3.2 ml/min, both p < 0.05). In comparison with groups 2 and 3, the response to both acetylcholine and adenosine was significantly impaired in patients with LVH. CONCLUSIONS: The current study demonstrates that hypertension with LVH is associated with both coronary vascular remodeling and attenuated endothelial and nonendothelial coronary flow reserve.