Francesco Romeo - Academia.edu (original) (raw)

Papers by Francesco Romeo

Research paper thumbnail of Relative Effects of α- and γ-Tocopherol on Low-Density Lipoprotein Oxidation and Superoxide Dismutase and Nitric Oxide Synthase Activity and Protein Expression in Rats

Journal of Cardiovascular Pharmacology and Therapeutics, 1999

... Reprint requests: Jawahar L. Mehta, MD, PhD, University of Flor-ida College of Medicine, 1600... more ... Reprint requests: Jawahar L. Mehta, MD, PhD, University of Flor-ida College of Medicine, 1600 Archer Rd., PO Box 100277 JHMHC ... the supernate were determined by monitoring the change in absorbance (234 nm) in a Perkin Elmer (Norwalk, CT) ultraviolet spectrophotometer. ...

Research paper thumbnail of Accuracy of thin-slice computed tomography in the detection of coronary stenoses

Our aim was to investigate the accuracy of multislice spiral computed tomography (MSCT) in the de... more Our aim was to investigate the accuracy of multislice spiral computed tomography (MSCT) in the detection of significant (>50%) coronary stenosis using a scanner equipped for 16 x 0.625 mm collimation. In 64 patients (59 male, mean age 58 +/- 5 years) with suspected coronary artery disease, MSCT (GE Light Speed-16, collimation: 16 x 0.625 mm) was performed 20 +/- 5 days before coronary angiography (CAG). Only angiographic segments >1.5 mm were considered for analysis. In all patients, MSCT was carried out without complications. Three patients were excluded from the analysis. Of 729 angiographic segments, 613 (84%) were judged evaluable by MSCT. Considering only the segments judged evaluable, the sensitivity was 89%, specificity 98%, positive predictive value 90%, and negative predictive value 98%. Including all segments in the analysis (evaluable and nonevaluable), sensitivity was 78%. Using a scanner with a collimation of 16 x 0.625 mm, our study confirms the potential role of MSCT in the detection of significant coronary stenosis with a sensitivity of 89% and a very high specificity (98%). Exclusion criteria and less than full evaluability of the coronary arteries must still be considered limitations of the method.

Research paper thumbnail of Verapamil versus acebutolol for syndrome X

American Journal of Cardiology, 1988

he precise mechanism responsible for angina pectoris in patients with syndrome X has not been com... more he precise mechanism responsible for angina pectoris in patients with syndrome X has not been completely identified. Recent evidence suggests that angina in these patients is probably due to an abnormal vasodilatory reserve of coronary microcirculation.1*2 This evidence and the clinical observation of an abnormally high pressure and heart rate response to low workload often seen in some patients with syndrome X suggest a role of an inappropriate sympathetic response in the pathogenesis of exercise-induced angina. To evaluate this aspect further, we carried out a randomized, double-blind, crossover study with acebutolol (a Pi-specific blocking agent) and verapamil.

Research paper thumbnail of Expression of lectin-like oxidized low-density lipoprotein receptors during ischemia-reperfusion and its role in determination of apoptosis and left ventricular dysfunction

Journal of The American College of Cardiology, 2003

Background-Oxidized LDL (Ox-LDL) seems to play key roles in atherogenesis. Lectinlike Ox-LDL rece... more Background-Oxidized LDL (Ox-LDL) seems to play key roles in atherogenesis. Lectinlike Ox-LDL receptor-1 (LOX-1)

Research paper thumbnail of Evaluation of Venous and Arterial Conduit Patency by 16Slice Spiral Computed Tomography

Research paper thumbnail of The effects of PPAR? ligand pioglitazone on platelet aggregation and arterial thrombus formation

Cardiovascular Research, 2005

Background: It has been suggested that peroxisome proliferator-activated receptor (PPAR)-g ligand... more Background: It has been suggested that peroxisome proliferator-activated receptor (PPAR)-g ligands reduce the development of atherosclerosis and myocardial ischemia-reperfusion injury; both of these phenomena are associated with platelet activation. We postulated that PPAR-g activation would inhibit platelet activation and intra-arterial thrombus formation. Methods and results: Sprague-Dawley rats were fed chow mixed with pioglitazone (1 or 10 mg/kg/day) for 7 to 10 days. A filter soaked in 30% FeCl 3 was applied around the abdominal aorta to study the patterns of arterial thrombogenesis. The aortic blood flow was continuously monitored using an ultrasonic Doppler flow probe. ADP and arachidonic acid-induced platelet aggregation and the expression of constitutive nitric oxide synthase (cNOS) and thrombomodulin in aorta were measured. Pioglitazone feeding delayed the time to occlusive thrombus formation by 40% ( Pb0.01 vs. control, n=9) without affecting the weight of the thrombus. ADP-as well as arachidonic acid-induced platelet aggregation was also inhibited by pioglitazone feeding ( Pb0.01 vs. control, n=9). Pioglitazone feeding also upregulated the aortic expression of cNOS and thrombomodulin; both are considered important factors in platelet aggregation and thrombus formation in vivo. The effect of a high dose (10 mg/kg/day) of pioglitazone was not more potent than that of a low dose (1 mg/kg/day). Conclusion: These results indicate that pioglitazone administration decreases platelet aggregation and delays intra-arterial thrombus formation in rats, at least partially, by an increase in the expression of cNOS and thrombomodulin.

Research paper thumbnail of Determinants of end-stage idiopathic dilated cardiomyopathy: A multivariate analysis of 104 patients

Clinical Cardiology, 1989

Our purpose in this study was to investigate the correlation of clinical, electrocardiographic, h... more Our purpose in this study was to investigate the correlation of clinical, electrocardiographic, hemodynamic, and histopathologic features at diagnosis with the long-term prognosis in 104 patients with idiopathic dilated cardiomyopathy to determine which factors are the independent determinants of the end-stage disease. During a mean follow-up of 3.8±3.5 years, 35 patients (33%) died, 14 (13%) suddenly and 21 (20%) from congestive heart failure. Univariate analysis of survival curves disclosed that clinical and electrocardiographic variables at diagnosis were similar in survivors and non-survivors. On the contrary, patients who subsequently died had higher mean right atrial pressure (p=0.0001), right ventricular end-diastolic pressure (p=0.0061), mean pulmonary artery pressure (p=0.0001), and left ventricular systolic (p=0.0049) and end-diastolic (p=0.0021) pressure than survivors. They also exhibited larger left ventricular end-diastolic (p=0.0046) and end-systolic (p=0.0027) volumes, lower ejection fraction (p=0.0001), and a greater proportion had severe mitral regurgitation (p=0.0095). Univariate analysis of histologic findings collected in a subgroup of patients referred since 1984 revealed a mild degree of myocellular hypertrophy to be associated with a poor prognosis (p=0.0217). Multivariate analysis selected only mean right atrial pressure (p=0.0022), ejection fraction (p=0.0089), and endsystolic volume (p=0.0265) as independent determinants of cardiac death. Our results suggest that cardiac catheterization is mandatory for risk stratification of patients with idiopathic dilated cardiomyopathy, since it allows the assessment of hemodynamic, angiographic, and histopathologic features helpful in identifying patients with a poor prognosis.

Research paper thumbnail of Inhibition of LOX1 by Statins May Relate to Upregulation of eNOS

Biochemical and Biophysical Research Communications, 2001

and atherosclerosis; both of these conditions are associated with diminished expression of consti... more and atherosclerosis; both of these conditions are associated with diminished expression of constitutive endothelial nitric oxide synthase (eNOS). Recent studies show that HMG CoA reductase inhibitors (statins) exert cardioprotective effect. We examined the role of LOX-1 in eNOS expression and modulation of this relationship by two different statins, simvastatin and atorvastatin in human coronary artery endothelial cells (HCAECs). Ox-LDL (40 g/ml) upregulated the expression of LOX-1; simultaneously, there was a reduction in eNOS expression. Pretreatment of HCAECs with simvastatin or atorvastatin (1 and 10 M) reduced ox-LDL-induced upregulation of LOX-1 and downregulation of eNOS (both P < 0.05). High concentration of statins (10 M) was more potent than the low concentration (1 M) (P < 0.05). Both statins also attenuated ox-LDL-mediated activation of MAP kinase. These observations indicate that statins attenuate the effect of ox-LDL on eNOS expression. Inhibitory effect on LOX-1 and subsequently MAP kinase activity provides a potential mechanism of beneficial effects of statins beyond lowering cholesterol.

Research paper thumbnail of Noninvasive coronary flow reserve assessed by transthoracic coronary Doppler ultrasound in patients with left anterior descending coronary artery stents

American Journal of Cardiology, 2003

Noninvasive measurement of coronary flow reserve (CFR) (hyperemic/flow velocity ratio at rest) by... more Noninvasive measurement of coronary flow reserve (CFR) (hyperemic/flow velocity ratio at rest) by transthoracic Doppler echocardiography showed normalization of flow in the left anterior descending (LAD) coronary artery early after stenting. We hypothesized that noninvasive CFR may reveal in-stent restenosis at follow-up. Therefore, we studied 134 patients, 0 to 72 months after successful proximal-middle LAD stenting, and 38 controls. LAD flow velocity was measured by transthoracic Doppler echocardiography during 90 seconds venous adenosine infusion (140 g/kg/min). CFR was measured in diastole. According to angiography, patients who received stents were divided into 3 groups: group I, <50% LAD in-stent restenosis (n ‫؍‬ 83); group II, nonsignificant (50% to 69%) LAD in-stent restenosis (n ‫؍‬ 17); and group III, significant (>70%) LAD in-stent restenosis (n ‫؍‬ 34). LAD CFR was similar in group I and controls (2.90 ؎ 0.58 vs 3.05 ؎ 0.81; p ‫؍‬ NS), it was slightly lower in group II (2.42 ؎ 0.33) compared with controls and group I (p <0.001 vs both), and clearly abnormal (<2) in group III (1.38 ؎ 0.48) compared with controls, and groups I and II (p <0.001). A CFR <2 had 91% sensitivity, 95% specificity, and 96% positive and 97% negative predictive values to detect significant stenosis in patients with LAD stents. Our data show that noninvasive Doppler assessment of CFR allows identification of significant LAD in-stent restenosis, based on a cut-off value of <2. ᮊ2003 by Excerpta Medica, Inc.

Research paper thumbnail of Lectin-like, oxidized low-density lipoprotein receptor-1 (LOX1): A critical player in the development of atherosclerosis and related disorders

LOX-1, a lectin-like 52-kD receptor for oxidized low-density lipoproteins (ox-LDL), is present pr... more LOX-1, a lectin-like 52-kD receptor for oxidized low-density lipoproteins (ox-LDL), is present primarily on endothelial cells. This receptor is upregulated by ox-LDL itself and by angiotensin II, endothelin, cytokines, and shear stress, all participants in atherosclerosis. This receptor is upregulated in the arteries of hypertensive, dyslipidemic, and diabetic animals. Upregulation of LOX-1 has been identified in atherosclerotic arteries of several animal species and humans, not only on the endothelial lining, but also in the neovasculature of the atherosclerotic plaque, and this receptor is often co-localized with apoptotic cells. Recent studies show upregulation of LOX-1 in the ischemic-reperfused myocardium. LOX-1 inhibition is associated with attenuation of atherosclerosis and associated ischemic injury. LOX-1 may be a novel, exciting target for drug therapy.

Research paper thumbnail of Unstable angina: Role of silent ischemia and total ischemic time (silent plus painful ischemia), a 6-year follow-up

Journal of The American College of Cardiology, 1992

To assess the long-term prognostic significance of total ischemic time (silent plus painful ische... more To assess the long-term prognostic significance of total ischemic time (silent plus painful ischemia) and silent ischemia in patients with unstable angina whose condition stabilized with medical treatment, 76 patients were studied. All patients underwent Holter ambulatory electrocardiographic (ECG) monitoring for greater than or equal to 48 h beginning within the 1st 12 h of the hospital stay. Forty-three patients (Group A) had a total ischemic time greater than or equal to 60 min, whereas 33 patients (Group B) had a total ischemic time less than 60 min. More than 78% of the ischemic episodes in patients in Group A and 62% of those in Group B were silent (p less than 0.05); nine patients in Group A and six in Group B had only silent episodes. Patients in Group A frequently showed three-vessel disease (65% vs. 18%, p less than 0.01), angiographic findings of subtotal occlusion of the coronary arteries (TIMI grade I) (76.7% vs. 42.4%, p less than 0.01) and ischemic alterations in the rest ECG (51.2% vs. 30.3%, p less than 0.05). During a 6-year follow-up period, 15 patients in Group A and 8 in Group B experienced myocardial infarction (p less than 0.05); 9 patients in Group A and 4 in Group B required coronary artery surgery (p less than 0.05) and 10 patients in Group A and 4 in Group B died of cardiac causes (p less than 0.01). Multivariate analysis showed three-vessel disease to be the most important predictor of cardiac mortality and morbidity (p = 0.025); it was followed in predictive power by a total ischemic time greater than or equal to 60 min and by left ventricular dysfunction. The presence of silent ischemia was not shown to be an independent predictor of long-term morbidity and mortality. In conclusion, patients with unstable angina and a total ischemic time greater than or equal to 60 min frequently have silent ischemic episodes on Holter ECG monitoring, a greater extent of coronary atherosclerosis and ischemic alterations of the rest ECG. The long-term prognosis of patients with unstable angina whose condition stabilizes with medical treatment depends on the extent of coronary atherosclerosis and on the longer duration of total ischemic time but not on the presence of silent ischemia.

Research paper thumbnail of Coronary recanalization in anterior myocardial infarction: the open perforator hypothesis

Acc Current Journal Review, 2003

Patent perforators, noninvasively imaged by transthoracic color-Doppler echocardiography, may ref... more Patent perforators, noninvasively imaged by transthoracic color-Doppler echocardiography, may reflect adequate reperfusion in anterior myocardial infarction (MI). BACKGROUND The Thrombolysis In Myocardial Infarction (TIMI) classification may not fully reflect adequate myocardial reperfusion in MI.

Research paper thumbnail of Different Isoforms of Tocopherols Enhance Nitric Oxide Synthase Phosphorylation and Inhibit Human Platelet Aggregation and Lipid Peroxidation: Implications in Therapy with Vitamin E

Journal of Cardiovascular Pharmacology and Therapeutics, 2001

alpha-Tocopherol has received much attention in the primary and secondary prevention of coronary ... more alpha-Tocopherol has received much attention in the primary and secondary prevention of coronary artery disease. Absence of other isoforms, such as gamma- and delta-tocopherol, in commercial preparations of vitamin E may account for the inconsistent results of clinical trials. Since platelet aggregation is intimately involved in thrombogenesis, the relative effects of alpha-, gamma-, and delta-tocopherol and their combination were examined on human platelet aggregation, lipid peroxidation, and constitutive nitric oxide synthase (cNOS) activity. Human platelets were incubated with the three different isoforms of tocopherol and their combination for 30 minutes, and then ADP-induced platelet aggregation measured. All three isoforms of tocopherol markedly and similarly decreased platelet aggregation in a concentration (120--480 microM)-dependent manner. All three tocopherols also decreased the level of the lipid peroxidation product, malondialdehyde (MDA), and increased NO release (P &lt; 0.05 vs control). These isoforms of tocopherol did not affect cNOS protein expression, but enhanced cNOS phosphorylation in platelets. The combination of three tocopherols in a concentration found in nature was more potent than alpha-, gamma-, or delta-tocopherol alone in this regard. These observations suggest that all three major isoforms of tocopherol have a similar effect on human platelet aggregation. The three isoforms appear to attenuate platelet aggregation at least in part via a decrease in free radical generation and an increase in platelet cNOS activity. The combination of tocopherols has a synergistic platelet inhibitory effect. Future clinical trials should concentrate on the combination of these three isoforms of tocopherols.

Research paper thumbnail of Multislice Computed Tomography in an Asymptomatic High-Risk Population

American Journal of Cardiology, 2007

Approximately 50% of all acute coronary syndromes occur in previously asymptomatic patients. This... more Approximately 50% of all acute coronary syndromes occur in previously asymptomatic patients. This study evaluated the value of multislice computed tomography for early detection of significant coronary artery disease (CAD) in high-risk asymptomatic subjects. One hundred sixty-eight asymptomatic subjects with ≥1 major risk factor (hypertension, diabetes, hypercholesterolemia, family history, or smoking) and an inconclusive or unfeasible noninvasive stress test result (stress electrocardiography, echocardiography, or nuclear scintigraphy) were evaluated in an outpatient setting. After clinical examination and laboratory risk analysis, all patients underwent multislice computed tomographic (MSCT) coronary angiography within 1 week. In all subjects, conventional coronary angiography was also carried out. Multislice computed tomography displayed single-vessel CAD in 16% of patients, 2-vessel CAD in 7%, and 3-vessel CAD in 4%. Selective coronary angiography confirmed the results of multislice computed tomography in 99% of all patients. Sensitivity and specificity of MSCT coronary angiography were 100% and 98%, respectively, with a positive predictive value of 95% and a negative predictive value of 100%. In conclusion, MSCT coronary angiography is an excellent noninvasive technique for early identification of significant CAD in high-risk asymptomatic patients with inconclusive or unfeasible noninvasive stress test results.

Research paper thumbnail of Oxidized LDL Upregulates Angiotensin II Type 1 Receptor Expression in Cultured Human Coronary Artery Endothelial Cells The Potential Role of Transcription Factor NF-kB

Research paper thumbnail of Regulatory role of endothelium in the expression of genes affecting arterial calcification

Biochemical and Biophysical Research Communications, 2004

Vascular calcification is a highly regulated process sharing features of bone mineralization. Sin... more Vascular calcification is a highly regulated process sharing features of bone mineralization. Since endothelium regulates many of the processes during atherogenesis, we monitored the expression of genes involved in calcification upon exposure of human coronary artery endothelial cells (HCAECs) to atherogenic stimuli. Genes studied were: core binding factor a-1 (Cbfa1/Runx2), a pivotal transcriptional regulator of osteogenesis; bone morphogenetic protein-2 (BMP2), an inducer of cartilage and bone; and matrix glaprotein (MGP), a potent inhibitor of calcification, which exerts its action by blocking BMP2. HCAECs were treated with oxidizedlow density lipoprotein (ox-LDL, 80 lg/mL) or tumor necrosis factor-a (TNFa, 10 ng/mL), and the expression of Cbfa1, BMP2, and MGP was quantified by real-time PCR. Cbfa1 was expressed at low levels in untreated HCAECs, and its expression did not change with ox-LDL or TNFa treatment. The expression of BMP2 and MGP increased early after exposure to ox-LDL or TNFa (at 2-8 h), and the increase was not evident at 24 h. Ox-LDL exerted a stronger effect on MGP than on BMP2 expression. The effects of ox-LDL, but not TNFa, on MGP and BMP2 expression were inhibited by pretreatment of cells with an antibody directed at LOX-1, a lectin-like receptor for ox-LDL (10 lg/mL). Thus, the endothelium, when exposed to atherogenic stimuli, ox-LDL in particular, regulates the process of calcification by enhancing the expression of the bone inhibitory MGP, while the expression of Cbfa1 remains unchanged. Upregulation of BMP2 may represent a feedback upregulation in response to increase in MGP. The effect of ox-LDL appears to be mediated by LOX-1 activation.

Research paper thumbnail of Relative Effects of α- and γ-Tocopherol on Low-Density Lipoprotein Oxidation and Superoxide Dismutase and Nitric Oxide Synthase Activity and Protein Expression in Rats

Journal of Cardiovascular Pharmacology and Therapeutics, 1999

... Reprint requests: Jawahar L. Mehta, MD, PhD, University of Flor-ida College of Medicine, 1600... more ... Reprint requests: Jawahar L. Mehta, MD, PhD, University of Flor-ida College of Medicine, 1600 Archer Rd., PO Box 100277 JHMHC ... the supernate were determined by monitoring the change in absorbance (234 nm) in a Perkin Elmer (Norwalk, CT) ultraviolet spectrophotometer. ...

Research paper thumbnail of Accuracy of thin-slice computed tomography in the detection of coronary stenoses

Our aim was to investigate the accuracy of multislice spiral computed tomography (MSCT) in the de... more Our aim was to investigate the accuracy of multislice spiral computed tomography (MSCT) in the detection of significant (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;50%) coronary stenosis using a scanner equipped for 16 x 0.625 mm collimation. In 64 patients (59 male, mean age 58 +/- 5 years) with suspected coronary artery disease, MSCT (GE Light Speed-16, collimation: 16 x 0.625 mm) was performed 20 +/- 5 days before coronary angiography (CAG). Only angiographic segments &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;1.5 mm were considered for analysis. In all patients, MSCT was carried out without complications. Three patients were excluded from the analysis. Of 729 angiographic segments, 613 (84%) were judged evaluable by MSCT. Considering only the segments judged evaluable, the sensitivity was 89%, specificity 98%, positive predictive value 90%, and negative predictive value 98%. Including all segments in the analysis (evaluable and nonevaluable), sensitivity was 78%. Using a scanner with a collimation of 16 x 0.625 mm, our study confirms the potential role of MSCT in the detection of significant coronary stenosis with a sensitivity of 89% and a very high specificity (98%). Exclusion criteria and less than full evaluability of the coronary arteries must still be considered limitations of the method.

Research paper thumbnail of Verapamil versus acebutolol for syndrome X

American Journal of Cardiology, 1988

he precise mechanism responsible for angina pectoris in patients with syndrome X has not been com... more he precise mechanism responsible for angina pectoris in patients with syndrome X has not been completely identified. Recent evidence suggests that angina in these patients is probably due to an abnormal vasodilatory reserve of coronary microcirculation.1*2 This evidence and the clinical observation of an abnormally high pressure and heart rate response to low workload often seen in some patients with syndrome X suggest a role of an inappropriate sympathetic response in the pathogenesis of exercise-induced angina. To evaluate this aspect further, we carried out a randomized, double-blind, crossover study with acebutolol (a Pi-specific blocking agent) and verapamil.

Research paper thumbnail of Expression of lectin-like oxidized low-density lipoprotein receptors during ischemia-reperfusion and its role in determination of apoptosis and left ventricular dysfunction

Journal of The American College of Cardiology, 2003

Background-Oxidized LDL (Ox-LDL) seems to play key roles in atherogenesis. Lectinlike Ox-LDL rece... more Background-Oxidized LDL (Ox-LDL) seems to play key roles in atherogenesis. Lectinlike Ox-LDL receptor-1 (LOX-1)

Research paper thumbnail of Evaluation of Venous and Arterial Conduit Patency by 16Slice Spiral Computed Tomography

Research paper thumbnail of The effects of PPAR? ligand pioglitazone on platelet aggregation and arterial thrombus formation

Cardiovascular Research, 2005

Background: It has been suggested that peroxisome proliferator-activated receptor (PPAR)-g ligand... more Background: It has been suggested that peroxisome proliferator-activated receptor (PPAR)-g ligands reduce the development of atherosclerosis and myocardial ischemia-reperfusion injury; both of these phenomena are associated with platelet activation. We postulated that PPAR-g activation would inhibit platelet activation and intra-arterial thrombus formation. Methods and results: Sprague-Dawley rats were fed chow mixed with pioglitazone (1 or 10 mg/kg/day) for 7 to 10 days. A filter soaked in 30% FeCl 3 was applied around the abdominal aorta to study the patterns of arterial thrombogenesis. The aortic blood flow was continuously monitored using an ultrasonic Doppler flow probe. ADP and arachidonic acid-induced platelet aggregation and the expression of constitutive nitric oxide synthase (cNOS) and thrombomodulin in aorta were measured. Pioglitazone feeding delayed the time to occlusive thrombus formation by 40% ( Pb0.01 vs. control, n=9) without affecting the weight of the thrombus. ADP-as well as arachidonic acid-induced platelet aggregation was also inhibited by pioglitazone feeding ( Pb0.01 vs. control, n=9). Pioglitazone feeding also upregulated the aortic expression of cNOS and thrombomodulin; both are considered important factors in platelet aggregation and thrombus formation in vivo. The effect of a high dose (10 mg/kg/day) of pioglitazone was not more potent than that of a low dose (1 mg/kg/day). Conclusion: These results indicate that pioglitazone administration decreases platelet aggregation and delays intra-arterial thrombus formation in rats, at least partially, by an increase in the expression of cNOS and thrombomodulin.

Research paper thumbnail of Determinants of end-stage idiopathic dilated cardiomyopathy: A multivariate analysis of 104 patients

Clinical Cardiology, 1989

Our purpose in this study was to investigate the correlation of clinical, electrocardiographic, h... more Our purpose in this study was to investigate the correlation of clinical, electrocardiographic, hemodynamic, and histopathologic features at diagnosis with the long-term prognosis in 104 patients with idiopathic dilated cardiomyopathy to determine which factors are the independent determinants of the end-stage disease. During a mean follow-up of 3.8±3.5 years, 35 patients (33%) died, 14 (13%) suddenly and 21 (20%) from congestive heart failure. Univariate analysis of survival curves disclosed that clinical and electrocardiographic variables at diagnosis were similar in survivors and non-survivors. On the contrary, patients who subsequently died had higher mean right atrial pressure (p=0.0001), right ventricular end-diastolic pressure (p=0.0061), mean pulmonary artery pressure (p=0.0001), and left ventricular systolic (p=0.0049) and end-diastolic (p=0.0021) pressure than survivors. They also exhibited larger left ventricular end-diastolic (p=0.0046) and end-systolic (p=0.0027) volumes, lower ejection fraction (p=0.0001), and a greater proportion had severe mitral regurgitation (p=0.0095). Univariate analysis of histologic findings collected in a subgroup of patients referred since 1984 revealed a mild degree of myocellular hypertrophy to be associated with a poor prognosis (p=0.0217). Multivariate analysis selected only mean right atrial pressure (p=0.0022), ejection fraction (p=0.0089), and endsystolic volume (p=0.0265) as independent determinants of cardiac death. Our results suggest that cardiac catheterization is mandatory for risk stratification of patients with idiopathic dilated cardiomyopathy, since it allows the assessment of hemodynamic, angiographic, and histopathologic features helpful in identifying patients with a poor prognosis.

Research paper thumbnail of Inhibition of LOX1 by Statins May Relate to Upregulation of eNOS

Biochemical and Biophysical Research Communications, 2001

and atherosclerosis; both of these conditions are associated with diminished expression of consti... more and atherosclerosis; both of these conditions are associated with diminished expression of constitutive endothelial nitric oxide synthase (eNOS). Recent studies show that HMG CoA reductase inhibitors (statins) exert cardioprotective effect. We examined the role of LOX-1 in eNOS expression and modulation of this relationship by two different statins, simvastatin and atorvastatin in human coronary artery endothelial cells (HCAECs). Ox-LDL (40 g/ml) upregulated the expression of LOX-1; simultaneously, there was a reduction in eNOS expression. Pretreatment of HCAECs with simvastatin or atorvastatin (1 and 10 M) reduced ox-LDL-induced upregulation of LOX-1 and downregulation of eNOS (both P < 0.05). High concentration of statins (10 M) was more potent than the low concentration (1 M) (P < 0.05). Both statins also attenuated ox-LDL-mediated activation of MAP kinase. These observations indicate that statins attenuate the effect of ox-LDL on eNOS expression. Inhibitory effect on LOX-1 and subsequently MAP kinase activity provides a potential mechanism of beneficial effects of statins beyond lowering cholesterol.

Research paper thumbnail of Noninvasive coronary flow reserve assessed by transthoracic coronary Doppler ultrasound in patients with left anterior descending coronary artery stents

American Journal of Cardiology, 2003

Noninvasive measurement of coronary flow reserve (CFR) (hyperemic/flow velocity ratio at rest) by... more Noninvasive measurement of coronary flow reserve (CFR) (hyperemic/flow velocity ratio at rest) by transthoracic Doppler echocardiography showed normalization of flow in the left anterior descending (LAD) coronary artery early after stenting. We hypothesized that noninvasive CFR may reveal in-stent restenosis at follow-up. Therefore, we studied 134 patients, 0 to 72 months after successful proximal-middle LAD stenting, and 38 controls. LAD flow velocity was measured by transthoracic Doppler echocardiography during 90 seconds venous adenosine infusion (140 g/kg/min). CFR was measured in diastole. According to angiography, patients who received stents were divided into 3 groups: group I, <50% LAD in-stent restenosis (n ‫؍‬ 83); group II, nonsignificant (50% to 69%) LAD in-stent restenosis (n ‫؍‬ 17); and group III, significant (>70%) LAD in-stent restenosis (n ‫؍‬ 34). LAD CFR was similar in group I and controls (2.90 ؎ 0.58 vs 3.05 ؎ 0.81; p ‫؍‬ NS), it was slightly lower in group II (2.42 ؎ 0.33) compared with controls and group I (p <0.001 vs both), and clearly abnormal (<2) in group III (1.38 ؎ 0.48) compared with controls, and groups I and II (p <0.001). A CFR <2 had 91% sensitivity, 95% specificity, and 96% positive and 97% negative predictive values to detect significant stenosis in patients with LAD stents. Our data show that noninvasive Doppler assessment of CFR allows identification of significant LAD in-stent restenosis, based on a cut-off value of <2. ᮊ2003 by Excerpta Medica, Inc.

Research paper thumbnail of Lectin-like, oxidized low-density lipoprotein receptor-1 (LOX1): A critical player in the development of atherosclerosis and related disorders

LOX-1, a lectin-like 52-kD receptor for oxidized low-density lipoproteins (ox-LDL), is present pr... more LOX-1, a lectin-like 52-kD receptor for oxidized low-density lipoproteins (ox-LDL), is present primarily on endothelial cells. This receptor is upregulated by ox-LDL itself and by angiotensin II, endothelin, cytokines, and shear stress, all participants in atherosclerosis. This receptor is upregulated in the arteries of hypertensive, dyslipidemic, and diabetic animals. Upregulation of LOX-1 has been identified in atherosclerotic arteries of several animal species and humans, not only on the endothelial lining, but also in the neovasculature of the atherosclerotic plaque, and this receptor is often co-localized with apoptotic cells. Recent studies show upregulation of LOX-1 in the ischemic-reperfused myocardium. LOX-1 inhibition is associated with attenuation of atherosclerosis and associated ischemic injury. LOX-1 may be a novel, exciting target for drug therapy.

Research paper thumbnail of Unstable angina: Role of silent ischemia and total ischemic time (silent plus painful ischemia), a 6-year follow-up

Journal of The American College of Cardiology, 1992

To assess the long-term prognostic significance of total ischemic time (silent plus painful ische... more To assess the long-term prognostic significance of total ischemic time (silent plus painful ischemia) and silent ischemia in patients with unstable angina whose condition stabilized with medical treatment, 76 patients were studied. All patients underwent Holter ambulatory electrocardiographic (ECG) monitoring for greater than or equal to 48 h beginning within the 1st 12 h of the hospital stay. Forty-three patients (Group A) had a total ischemic time greater than or equal to 60 min, whereas 33 patients (Group B) had a total ischemic time less than 60 min. More than 78% of the ischemic episodes in patients in Group A and 62% of those in Group B were silent (p less than 0.05); nine patients in Group A and six in Group B had only silent episodes. Patients in Group A frequently showed three-vessel disease (65% vs. 18%, p less than 0.01), angiographic findings of subtotal occlusion of the coronary arteries (TIMI grade I) (76.7% vs. 42.4%, p less than 0.01) and ischemic alterations in the rest ECG (51.2% vs. 30.3%, p less than 0.05). During a 6-year follow-up period, 15 patients in Group A and 8 in Group B experienced myocardial infarction (p less than 0.05); 9 patients in Group A and 4 in Group B required coronary artery surgery (p less than 0.05) and 10 patients in Group A and 4 in Group B died of cardiac causes (p less than 0.01). Multivariate analysis showed three-vessel disease to be the most important predictor of cardiac mortality and morbidity (p = 0.025); it was followed in predictive power by a total ischemic time greater than or equal to 60 min and by left ventricular dysfunction. The presence of silent ischemia was not shown to be an independent predictor of long-term morbidity and mortality. In conclusion, patients with unstable angina and a total ischemic time greater than or equal to 60 min frequently have silent ischemic episodes on Holter ECG monitoring, a greater extent of coronary atherosclerosis and ischemic alterations of the rest ECG. The long-term prognosis of patients with unstable angina whose condition stabilizes with medical treatment depends on the extent of coronary atherosclerosis and on the longer duration of total ischemic time but not on the presence of silent ischemia.

Research paper thumbnail of Coronary recanalization in anterior myocardial infarction: the open perforator hypothesis

Acc Current Journal Review, 2003

Patent perforators, noninvasively imaged by transthoracic color-Doppler echocardiography, may ref... more Patent perforators, noninvasively imaged by transthoracic color-Doppler echocardiography, may reflect adequate reperfusion in anterior myocardial infarction (MI). BACKGROUND The Thrombolysis In Myocardial Infarction (TIMI) classification may not fully reflect adequate myocardial reperfusion in MI.

Research paper thumbnail of Different Isoforms of Tocopherols Enhance Nitric Oxide Synthase Phosphorylation and Inhibit Human Platelet Aggregation and Lipid Peroxidation: Implications in Therapy with Vitamin E

Journal of Cardiovascular Pharmacology and Therapeutics, 2001

alpha-Tocopherol has received much attention in the primary and secondary prevention of coronary ... more alpha-Tocopherol has received much attention in the primary and secondary prevention of coronary artery disease. Absence of other isoforms, such as gamma- and delta-tocopherol, in commercial preparations of vitamin E may account for the inconsistent results of clinical trials. Since platelet aggregation is intimately involved in thrombogenesis, the relative effects of alpha-, gamma-, and delta-tocopherol and their combination were examined on human platelet aggregation, lipid peroxidation, and constitutive nitric oxide synthase (cNOS) activity. Human platelets were incubated with the three different isoforms of tocopherol and their combination for 30 minutes, and then ADP-induced platelet aggregation measured. All three isoforms of tocopherol markedly and similarly decreased platelet aggregation in a concentration (120--480 microM)-dependent manner. All three tocopherols also decreased the level of the lipid peroxidation product, malondialdehyde (MDA), and increased NO release (P &lt; 0.05 vs control). These isoforms of tocopherol did not affect cNOS protein expression, but enhanced cNOS phosphorylation in platelets. The combination of three tocopherols in a concentration found in nature was more potent than alpha-, gamma-, or delta-tocopherol alone in this regard. These observations suggest that all three major isoforms of tocopherol have a similar effect on human platelet aggregation. The three isoforms appear to attenuate platelet aggregation at least in part via a decrease in free radical generation and an increase in platelet cNOS activity. The combination of tocopherols has a synergistic platelet inhibitory effect. Future clinical trials should concentrate on the combination of these three isoforms of tocopherols.

Research paper thumbnail of Multislice Computed Tomography in an Asymptomatic High-Risk Population

American Journal of Cardiology, 2007

Approximately 50% of all acute coronary syndromes occur in previously asymptomatic patients. This... more Approximately 50% of all acute coronary syndromes occur in previously asymptomatic patients. This study evaluated the value of multislice computed tomography for early detection of significant coronary artery disease (CAD) in high-risk asymptomatic subjects. One hundred sixty-eight asymptomatic subjects with ≥1 major risk factor (hypertension, diabetes, hypercholesterolemia, family history, or smoking) and an inconclusive or unfeasible noninvasive stress test result (stress electrocardiography, echocardiography, or nuclear scintigraphy) were evaluated in an outpatient setting. After clinical examination and laboratory risk analysis, all patients underwent multislice computed tomographic (MSCT) coronary angiography within 1 week. In all subjects, conventional coronary angiography was also carried out. Multislice computed tomography displayed single-vessel CAD in 16% of patients, 2-vessel CAD in 7%, and 3-vessel CAD in 4%. Selective coronary angiography confirmed the results of multislice computed tomography in 99% of all patients. Sensitivity and specificity of MSCT coronary angiography were 100% and 98%, respectively, with a positive predictive value of 95% and a negative predictive value of 100%. In conclusion, MSCT coronary angiography is an excellent noninvasive technique for early identification of significant CAD in high-risk asymptomatic patients with inconclusive or unfeasible noninvasive stress test results.

Research paper thumbnail of Oxidized LDL Upregulates Angiotensin II Type 1 Receptor Expression in Cultured Human Coronary Artery Endothelial Cells The Potential Role of Transcription Factor NF-kB

Research paper thumbnail of Regulatory role of endothelium in the expression of genes affecting arterial calcification

Biochemical and Biophysical Research Communications, 2004

Vascular calcification is a highly regulated process sharing features of bone mineralization. Sin... more Vascular calcification is a highly regulated process sharing features of bone mineralization. Since endothelium regulates many of the processes during atherogenesis, we monitored the expression of genes involved in calcification upon exposure of human coronary artery endothelial cells (HCAECs) to atherogenic stimuli. Genes studied were: core binding factor a-1 (Cbfa1/Runx2), a pivotal transcriptional regulator of osteogenesis; bone morphogenetic protein-2 (BMP2), an inducer of cartilage and bone; and matrix glaprotein (MGP), a potent inhibitor of calcification, which exerts its action by blocking BMP2. HCAECs were treated with oxidizedlow density lipoprotein (ox-LDL, 80 lg/mL) or tumor necrosis factor-a (TNFa, 10 ng/mL), and the expression of Cbfa1, BMP2, and MGP was quantified by real-time PCR. Cbfa1 was expressed at low levels in untreated HCAECs, and its expression did not change with ox-LDL or TNFa treatment. The expression of BMP2 and MGP increased early after exposure to ox-LDL or TNFa (at 2-8 h), and the increase was not evident at 24 h. Ox-LDL exerted a stronger effect on MGP than on BMP2 expression. The effects of ox-LDL, but not TNFa, on MGP and BMP2 expression were inhibited by pretreatment of cells with an antibody directed at LOX-1, a lectin-like receptor for ox-LDL (10 lg/mL). Thus, the endothelium, when exposed to atherogenic stimuli, ox-LDL in particular, regulates the process of calcification by enhancing the expression of the bone inhibitory MGP, while the expression of Cbfa1 remains unchanged. Upregulation of BMP2 may represent a feedback upregulation in response to increase in MGP. The effect of ox-LDL appears to be mediated by LOX-1 activation.