A man with four coronary arteries.
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Coronary Angiography↗
Biomedical subjects
Jawahar L Mehta
Publications and source records attributed to Jawahar L Mehta.
Modulation of atherosclerosis, blood pressure and arterial elasticity by statins.
It is well known that dyslipidemia and hypertension frequently coexist. There is increasing recognition of a mutually facilitative interaction between dyslipidemia and renin- angiotensin system (RAS) activation in the development of atherosclerosis. Both of these systems share many of the same properties in terms of activation of pro-inflammatory, pro-oxidant and pro-atherosclerosis pathways. Statins in particular have been shown to influence the biology of endothelial cells, vascular smooth muscle cells and constituents of the interstitial matrix, particularly fibroblasts. It is no wonder that concurrent therapy of dyslipidemia with statins enhances the effects of RAS inhibitors. Although the effects of statins on the regulation of determinants of vascular stiffness are not well defined, it is quite likely that these regulatory pathways will be influenced by dyslipidemia therapy, especially statins.
Atherosclerosis↗
Oxidized or native low-density lipoprotein cholesterol: which is more important in atherogenesis?
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Atherosclerosis↗
Comparison of mortality rates in statin users versus nonstatin users in a United States veteran population.
Statins have been shown to be effective in reducing cardiovascular events and overall mortality in primary and secondary prevention trials. This study was designed to examine the effect of statin use on overall death. Cross-sectional data were obtained from the Department of Veterans Affairs Veterans Integrated Service Network 16 database for approximately 1.5 million veterans followed up in 10 hospitals in the southern United States. Statins were prescribed more often to elderly subjects with a history of coronary artery disease, hypertension, diabetes mellitus, current smoking, and using cardiovascular drugs (beta blockers, aspirin, angiotensin-converting enzyme inhibitors, and calcium channel blockers). The predictors of death were, as expected, cancer, diabetes mellitus, the use of cardiac drugs, and age. Importantly, using statins showed a highly significant negative association with death (odds ratio 0.54, 95% confidence interval 0.42 to 0.69, p <0.0001), even after adjustment for all other variables. Overall, the mean age at death among statin users was 2 years older than among nonstatin users, despite statin users being at a higher risk of death. In conclusion, the results of this study have shown that using statins is a potent life-saving strategy. The benefit observed in this study is unique because almost 1/2 the patients were >or=70 years of age when statin therapy was initiated.
Adrenergic beta-Antagonists↗
Enhanced 11beta-hydroxysteroid dehydrogenase activity, the metabolic syndrome, and systemic hypertension.
Metabolic syndrome, with its attendant cardiovascular complications, is reaching epidemic proportions worldwide; hence, there is intense interest in understanding the pathogenesis of and developing therapy for these common disorders. Recent studies have suggested that metabolic syndrome may be a stress response, with an underlying abnormality in the enzyme 11beta-hydroxysteroid dehydrogenase. At the cellular level, the enzyme hydroxysteroid dehydrogenase type 1 (HSD1) locally regenerates active cortisol from inactive cortisone, amplifying glucocorticoid receptor activation and promoting preadipocyte differentiation and adipocyte hypertrophy. Although initial studies in transgenic mice and humans are encouraging, more data are required to conclusively prove the hypothesis that the adipose-tissue-specific overexpression of HSD1 and the resultant increase in tissue-specific cortisol concentrations result in human obesity, insulin resistance, high blood pressure, and metabolic syndrome. Currently, selective inhibitors of HSD1 are not available for human use; however, their development is under way. The use of potent and selective HSD1 inhibitors will finally confirm or refute this hypothesis and may turn out to be an effective strategy for combating these common maladies.
11-beta-Hydroxysteroid Dehydrogenases↗
Relation of microalbuminuria and coronary artery disease in patients with and without diabetes mellitus.
Microalbuminuria (MA) is a well-known risk factor for coronary artery disease (CAD) in diabetics and nondiabetics. It is associated with higher cardiovascular mortality, especially in diabetics. However, there are few data linking angiographic severity of CAD to microalbuminuria. We examined coronary angiograms for extent of severe CAD (luminal narrowing > or = 50%) in patients with type 2 diabetes mellitus (DM) and MA (DM+MA+, n = 101), patients with DM and without MA (DM+MA-, n = 101), patients without DM and with MA (DM-MA+, n = 64), and patients without DM and MA (DM-MA-, n = 64). We also evaluated fasting glucose levels in all patients and glycosylated hemoglobin in diabetics. Patients' mean age in the DM+MA+, DM+MA-, DM-MA+, and DM-MA- groups was similar. Gender distribution across the 4 groups was also not significantly different. There were no significant differences in the prevalence of hypertension, hypercholesterolemia, and current smoking across the 4 groups. The presence of 2- or 3-vessel CAD showed a linear increase from group DM-MA- to group DM+MA+ (p < 0.001). Diabetics with MA had higher fasting glucose and glycosylated hemoglobin levels than diabetics without MA (p < 0.001). Thus, patients with MA have more severe angiographic CAD than those without MA. This relation is independent of other risk factors and is particularly evident in patients with DM.
Aged↗
Angiotensin II-mediated oxidative stress and procollagen-1 expression in cardiac fibroblasts: blockade by pravastatin and pioglitazone.
Angiotensin II (ANG II), a product of renin-angiotensin system activation, enhances collagen synthesis, which is a key event in cardiac remodeling after myocardial infarction. Inhibition of cardiac remodeling is now a target of multiple therapies, including 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, commonly known as statins, and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands. We examined the potential antifibrotic effect of the combination of a statin (pravastatin) and a PPAR-gamma ligand (pioglitazone) in ANG II-treated mouse cardiac fibroblasts. ANG II treatment induced procollagen-1 expression, which was inhibited by pravastatin and pioglitazone in a dose-dependent fashion. Pretreatment of fibroblasts with low therapeutic concentrations of either pravastatin (0.1 microM) or pioglitazone (5 microM) only slightly decreased ANG II-induced NADPH oxidase expression, superoxide anion production, and procollagen-1 expression; however, the combination of pravastatin and pioglitazone markedly modulated these effects of ANG II. The combination also blocked ANG II-mediated p38 MAPK and p44/42 MAPK activation. Electrophoretic mobility shift assay showed that ANG II activated transcription factors NF-kappaB and activator protein-1 (AP-1). Although pravastatin and pioglitazone alone had a variable effect on NF-kappaB and AP-1 activation, their combination exerted a potent inhibitory effect on the activation of both NF-kappaB and AP-1. The effects of pravastatin and pioglitazone in combination on superoxide generation and procollagen-1 expression mimicked those of alpha-tocopherol and gamma-tocopherol, two potent antioxidants. Thus it appears that there is a positive interaction between pravastatin and pioglitazone in modulating ANG II-mediated oxidative stress, inhibiting MAPK activation, and procollagen-1 expression.
Angiotensin II↗
OLR1 gene and coronary artery disease/acute myocardial infarction: replication in an independently collected sample.
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Acute Disease↗
Suppression of atherogenesis by delivery of TGFbeta1ACT using adeno-associated virus type 2 in LDLR knockout mice.
TGFbeta(1) deficiency has been attributed to the development of atherosclerosis. There is, however, little direct evidence for this concept. To examine this hypothesis, low-density lipoprotein receptor knockout (LDLR(-/-)) mice were injected via tail vein with recombinant adeno-associated virus type 2 (rAAV) carrying a bioactive TGFbeta(1) mutant (AAV/TGFbeta1ACT, n=10) or granulocyte-macrophage-colony stimulating factor (AAV/GM-CSF, n=10, a negative control) or saline (n=9, control), and then put on a high cholesterol diet. At 18 weeks, blood lipids were found to be similarly elevated in all LDLR(-/-) mice. TGFbeta1ACT and GM-CSF (DNA, mRNA, and protein) were highly expressed in the tissues of mice given TGFbeta1ACT or AAV/GM-CSF, respectively, showing sustained transfection following gene delivery by the systemic route. Saline-treated and AAV/GM-CSF-treated LDLR(-/-) mice showed extensive areas of atherosclerotic lesion formation. There was evidence of intense oxidative stress (nitrotyrosine staining), inflammation (CD68 staining), and expression of adhesion molecules and the ox-LDL receptor LOX-1 (gene array analysis) in the atherosclerotic tissues. Importantly, atherosclerotic lesion formation was markedly inhibited in the LDLR(-/-) mice given AAV/TGFbeta1ACT. Expression of adhesion molecules and LOX-1, oxidative stress, and inflammatory response all were inhibited in the mice given AAV/TGFbeta1ACT (P<0.05 vs. saline-treated or GM-CSF-treated LDLR(-/-) mice). These data for the first time demonstrate that systemic delivery of TGFbeta1ACT gene via AAV can inhibit formation of atherosclerotic lesions, possibly via anti-inflammatory and anti-oxidant mechanisms. These findings suggest a novel view of TGFbeta(1) in atherogenesis and a potential new gene therapy for treatment of atherosclerosis.
Adenoviridae↗
Molecular dissection of angiotensin II-activated human LOX-1 promoter.
OBJECTIVE: LOX-1, a receptor for oxidized low-density lipoprotein, plays a critical role in atherosclerosis. Its expression is upregulated by pro-atherogenic stimuli, such as angiotensin II (Ang II). In this study, we explored LOX-1 transcriptional promoter activation in response to Ang II in human coronary artery endothelial cells (HCAECs). METHODS AND RESULTS: We constructed full-length and deletion LOX-1 promoter mutants and examined their activation in response to Ang II in HCAECs. The Ang II (1 micromol/L for 24 hours) markedly induced LOX-1 promoter activity beyond the basal level, and a 116-bp fragment (between nt -2247 and -2131) was necessary for this induction. Within this 116-bp promoter fragment, there is a potential binding motif for transcription factor NF-kappaB. By EMSA, we observed the activation of NF-kappaB by Ang II. The critical role of NF-kappaB in Ang II-induced LOX-1 promoter activation was confirmed by mutagenesis assay, and further confirmed by blocking NF-kappaB activation with the NF-kappaB inhibitor caffeic acid phenethyl ester or NF-kappaB p65 siRNA. CONCLUSIONS: This study strongly suggests that Ang II, by activating NF-kappaB, induces LOX-1 promoter activation.
Angiotensin II↗
Oxidative stress in diabetes: a mechanistic overview of its effects on atherogenesis and myocardial dysfunction.
Diabetes is a major risk factor for atherosclerosis. Atherogenesis involves endothelial dysfunction, activation and injury, inflammation, and smooth muscle cell migration and proliferation. Platelet activation in the narrowed arteries is the most proximate event in the culmination of an acute event such as acute myocardial infraction and stroke. Hyperglycemia is associated with all these adverse events in the process of genesis of atherosclerosis. The effect of diabetes (hyperglycemia) is mediated in large part by the state of enhanced oxidative stress, which is not counter-balanced by endogenous antioxidants. This paper reviews the ignition of oxidative stress in diabetes and the mediation of events leading to atherogenesis.
Animals↗
Safety and effectiveness of granulocyte-colony stimulating factor in mobilizing stem cells and improving cytokine profile in advanced chronic heart failure.
The objective of this study was to determine a safe and effective dose of granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells in patients with advanced heart failure and to determine its effects on the cytokine profile. Patients with advanced heart failure (n = 6) and implantable defibrillators in situ were administered G-CSF after baseline echocardiographic and laboratory evaluation, using an escalating dose schedule designed to ensure safety. The peripheral CD34+ hematopoietic stem cell count increased from 3.6 +/- 0.5/microl to 38.7 +/- 13/microl (p= 0.022) after 5 days of 5 microg/kg/day G-CSF therapy. The baseline or peak white blood cell count did not predict the stem cell response. G-CSF increased plasma levels of interleukin-10. Left ventricular ejection fraction increased significantly in the 4 patients with ischemic cardiomyopathy 9 months after treatment. No major adverse effects attributable to the drug occurred during administration or 9 months of follow-up. Our results have shown that low-dose G-CSF significantly mobilized hematopoietic stem cells in advanced heart failure and improved left ventricular function in the ischemic subset of patients. G-CSF significantly increased plasma levels of the anti-inflammatory cytokine interleukin-10, without changing pro-inflammatory cytokine levels. In conclusion, these results indicate a novel mechanism of action for the potential therapeutic benefit of G-CSF in advanced ischemic cardiomyopathy.
Aged↗
Common carotid arterial interadventitial distance (diameter) as an indicator of the damaging effects of age and atherosclerosis, a cross-sectional study of the Atherosclerosis Risk in Community Cohort Limited Access Data (ARICLAD), 1987-89.
BACKGROUND: The effect of age on common carotid artery diameter is unclear for varying atherosclerosis risk levels. METHODS: Cross-sectional data from the Atherosclerosis Risk in Communities Limited Access Data set were used to estimate the association of age with B-mode ultrasound common carotid artery diameter for three atherosclerosis risk levels. Based on information from clinical examinations, B-mode ultrasounds, questionnaires, blood and other tests, participants were categorized into three groups: pre-existing disease (prevalent stroke and/or coronary heart disease), high risk group (no pre-existing disease, but prevalent diabetes, hypertension, plaques/shadowing, body mass index > or = 30, current smoking, or hyperlipidemia), and a low risk group (no pre-existing disease, no plaques/shadowing, and no major elevated risk factors). Multivariable linear regression analyses modeled the common carotid artery diameter relationship with age. RESULTS: Age was positively and significantly associated with common carotid artery diameter after risk factor adjustment in the overall sample, but age had a larger effect among persons with evidence of atherosclerosis (interaction p < 0.05). Each year of older age was associated with 0.03 mm larger diameter/year among persons with pre-existing disease, with 0.027 mm larger diameter/year in the high risk group, but only 0.017 mm/year among the low risk group. Results were qualitatively similar using plaques/shadowing status to indicate atherosclerosis severity. CONCLUSION: The significant impact of age on common carotid artery diameter among low risk, middle-aged, black and white men and women suggests arterial remodelling may occur in the absence of identified risk factors. The significantly larger impact of age among persons with, compared to persons without identified atherosclerosis or its risk factors, suggests that arterial remodelling may be an indicator of exposure duration.
Adult↗
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) transcriptional regulation by Oct-1 in human endothelial cells: implications for atherosclerosis.
LOX-1, a receptor for ox-LDL (oxidized low-density lipoprotein), has recently been determined to play a critical role in the progression of atherosclerosis. LOX-1 expression (mRNA and protein) has been shown to be up-regulated by pro-atherogenic stimuli, such as ox-LDL and Ang II (angiotensin II). However, the molecular mechanisms of these up-regulations are unclear. In the present study, we explored LOX-1 transcriptional promoter activation in response to ox-LDL and Ang II. Under basal states, LOX-1 core promoter (LOX-1 -35/+36) was found to be sufficient for its basal activity in HCAECs (human coronary artery endothelial cells). More importantly, we found that ox-LDL (60 microg/ml for 24 h) induced LOX-1 promoter activity significantly and that a 105 bp fragment (between nt -1599 and -1494) was required for this activation. Within this 106 bp fragment, there is a potential binding motif for the transcription factor Oct-1 (octamer-1). By electrophoretic mobility-shift assay, we observed the activation of Oct-1 by ox-LDL. The critical role of Oct-1 in ox-LDL-induced LOX-1 promoter activation was further confirmed by mutagenesis assay. For comparison, we also examined LOX-1 promoter activation in response to Ang II (1 micromol/l for 24 h). Interestingly, another promoter region, between nt -2336 and -1990, was required for Ang II-induced LOX-1 promoter activation. In conclusion, the present study strongly suggests that ox-LDL, by activating Oct-1, induces LOX-1 promoter activation. Furthermore, this study suggests that while ox-LDL and Ang II both induce LOX-1 expression in HCAECs, the underlying mechanisms of promoter activation are different from each other.
Angiotensin II↗
Structural evaluation of radially expandable cardiovascular stents encased in a polyurethane film.
A method of encasing cardiovascular stents with an expandable polyurethane coating has been developed to provide a smooth homogeneous inner wall allowing for a confluent growth of endothelial cells. In this design, the metal wire stent structure is completely covered by the polyurethane film, minimizing biocorrosion of the metal (stainless steel or nitinol), and providing a homogeneous surface for surface treatment and incorporation of various eluting drugs to prevent platelet aggregation while supporting endothelialization. The polyurethane surface was treated with a helium plasma for sterilization and promotes growth of cells. The article details the performance of the coated film to expand with the metal stent up to 225% during deployment. Stress/strain behavior of polyurethane films, subsequent plasma treatment of the surface, and the adhesion of the coating to the stent structure upon expansion are presented. A film of less than 25 microm was found to be sufficient for corrosion resistance and flexibility without producing any excess stress on the stent structure. Straining the film to 225% and plasma modification did not affect the mechanical and surface properties, but allowed for improved biocompatibility as determined by the critical surface tension, surface chemistry, and roughness.
Arteries↗
Interaction of oxidized low-density lipoprotein and the renin-angiotensin system in coronary artery disease.
Hyperlipidemia and hypertension are frequently observed in patients with coronary artery disease. It has been proposed that an interaction between low-density lipoprotein, especially its oxidized form (ox-LDL), and renin-angiotensin system (RAS) activation is a major determinant of atherogenesis. Ox-LDL accumulation in the blood vessels enhances the expression and activation of RAS components; on the other hand, activation of RAS stimulates the accumulation of LDL and its oxidation into ox-LDL in the blood vessels. Individually ox-LDL and RAS activation induce oxidative stress and inflammatory cascade, whereas their combination exerts a synergistic effect. This concept of cross-talk between ox-LDL/hyperlipidemia and RAS activation has been proven in laboratory animals. Clinical trials also suggest that blockade of hyperlipidemia and RAS may have a synergistic salutary effect on the outcome of patients with hypertension and/or manifestations of atherosclerosis. This concept needs to be evaluated further in large clinical studies.
Animals↗
The role of statins in endothelial dysfunction in hypertension.
PURPOSE OF REVIEW: Hypertension and dyslipidemia frequently coexist, and endothelial dysfunction is associated with the pathophysiology of both atherosclerosis and hypertension. Evidence is convincing for an overlapping role of oxidative stress, renin-angiotensin system activation, and dyslipidemia in the genesis of endothelial dysfunction. RECENT FINDINGS: Ample experimental and human data suggest that common cellular pathways are involved in the pathogenesis of hypertension, increased vascular resistance, and plaque formation. Multiple interventions such as dietary modification, exercise, antioxidants, and antihypertensive drugs improve endothelial dysfunction in hypertension. Statin drugs are a cornerstone of dyslipidemia therapy. Studies have demonstrated that statins correct endothelial function and vascular stiffening and may be useful in reducing blood pressure to target levels. SUMMARY: Statins may be a useful adjunct in the treatment of hypertension in patients with dyslipidemia and possibly those with normal cholesterol levels.
Antihypertensive Agents↗
Prevention of heart failure.
PURPOSE OF REVIEW: Chronic heart failure imposes a significant health burden and remains a substantial and increasing problem despite advances in therapy. Hence, prevention of heart failure is a priority. RECENT FINDINGS: Various risk factors have been identified that contribute to the development of heart failure. In this review, we will discuss the various recently reported clinical trials, epidemiological studies, meta-analyses, and subanalyses that have identified these risk factors and have provided evidence regarding the strategies to prevent heart failure. SUMMARY: Heart failure is a costly, disabling, and potentially fatal disease. It is therefore important to incorporate the strategies for prevention of heart failure on the basis of the current available evidence into routine clinical practice.
Atherosclerosis↗