Publications by authors named "Rajat S Barua"

24 Publications

  • Page 1 of 1

Is There a Role for Combined Use of Varenicline and Nicotine Patch or Extended Treatment Duration to Enhance Smoking Cessation?

JAMA 2021 10;326(15):1481-1482

Department of Cardiovascular Medicine, University of Kansas Medical Center, Kansas City.

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http://dx.doi.org/10.1001/jama.2021.14994DOI Listing
October 2021

The Effects of Vitamin D Supplementation and 25-Hydroxyvitamin D Levels on the Risk of Myocardial Infarction and Mortality.

J Endocr Soc 2021 Oct 15;5(10):bvab124. Epub 2021 Jul 15.

Department of Cardiovascular Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.

Objective: The aim of the study was to examine the effects of the vitamin D (Vit-D) treatment and nontreatment on Vit-D-deficient patients without a prior history of myocardial infarction (MI).

Materials And Methods: This was a retrospective, observational, nested case-control study of patients (N = 20 025) with low 25-hydroxyvitamin D ([25-OH]D) levels (<20 ng/mL) who received care at the Veterans Health Administration from 1999 to 2018. Patients were divided into 3 groups: Group A (untreated, levels ≤20 ng/mL), Group B (treated, levels 21-29 ng/mL), and Group C (treated, levels ≥30 ng/mL). The risk of MI and all-cause mortality were compared utilizing propensity score-weighted Cox proportional hazard models.

Results: Among the cohort of 20 025 patients, the risk of MI was significantly lower in Group C than in Group B (hazard ratio [HR] 0.65, 95% CI 0.49-0.85,  = .002) and Group A (HR 0.73, 95% CI 0.55-0.96),  = .02). There was no difference in the risk of MI between Group B and Group A (HR 1.14, 95% CI 0.91-1.42,  = 0.24). Compared with Group A, both Group B (HR 0.59, 95% CI 0.54-0.63,  < .001) and Group C (HR 0.61, 95% CI 0.56-0.67,  < .001) had significantly lower all-cause mortality. There was no difference in all-cause mortality between Group B and Group C (HR 0.99, 95% CI 0.89-1.09,  = .78).

Conclusions: In patients with Vit-D deficiency and no prior history of MI, treatment to the (25-OH)D level of >20 ng/mL and >30 ng/mL was associated with a significantly lower risk of all-cause mortality. The lower risk of MI was observed only in individuals maintaining (25-OH)D levels ≥30 ng/mL.
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http://dx.doi.org/10.1210/jendso/bvab124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358990PMC
October 2021

Reducing Tobacco-Related Disability in Chronic Smokers.

Am J Med 2020 08 20;133(8):908-915. Epub 2020 Apr 20.

University of Kansas Medical Center, Kansas City Veterans' Administration, Kansas City, Mo.

Tobacco consumption (predominantly cigarettes) is the leading preventable cause of mortality worldwide. Although the major focus of strategies to reduce mortality from tobacco must include prevention of future generations from initially gaining access, some smokers are unwilling or unable to quit. Can the higher risk chronic smoker be identified and can their risk be reduced? The risk of adverse events in cigarette smokers is influenced by the intensity and duration of cigarette smoking or secondhand exposure, associated conventional risk factors, environmental stressors, and certain genetic variants and epigenetic modifiers. Recent data suggest that inflammatory markers such as high-sensitivity C-reactive protein (hs CRP) and targeted imaging can identify some smokers at higher risk. As smoking is prothrombotic, aspirin initiation and expanded statin use might reduce cardiovascular risk in those who do not presently meet criteria for these therapies, but further study is required. Thus, although advocacy for smoking cessation should always be the primary approach, increased efforts are needed to identify and potentially treat those who are unable or unwilling to quit.
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http://dx.doi.org/10.1016/j.amjmed.2020.03.025DOI Listing
August 2020

Relation of Testosterone Normalization to Mortality and Myocardial Infarction in Men With Previous Myocardial Infarction.

Am J Cardiol 2019 10 25;124(8):1171-1178. Epub 2019 Jul 25.

Division of Cardiovascular Research, Kansas City VA Medical Center, Kansas City, Missouri; Department of Cardiovascular Medicine, University of Kansas Medical Center, Kansas City, Kansas; Division of Cardiovascular Medicine, Kansas City VA Medical Center, Kansas City, Missouri. Electronic address:

The effect of normalization of serum testosterone levels with testosterone replacement therapy (TRT) in patients with a history of myocardial infarction (MI) is unknown. The objective of this study was to determine the incidence of recurrent MI and all-cause mortality in subjects with a history of MI and low total testosterone (TT) with and without TRT. We retrospectively examined 1,470 men with documented low TT levels and previous MI, categorized into Gp1: TRT with normalization of TT levels (n = 755) Gp2: TRT without normalization of TT levels (n = 542), and Gp3: no TRT (n = 173). The association of TRT with all-cause mortality and recurrent MI was compared using propensity score-weighted Cox proportional hazard models. All-cause mortality was lower in Gp1 versus Gp2 (hazard ratio [HR] 0.76, confidence interval [CI] 0.64 to 0.90, p = 0.002), and Gp1 versus Gp3 (HR 0.76, CI 0.60 to 0.98, p = 0.031). There was no significant difference in the risk of death between Gp2 versus Gp3 (HR 0.97, CI 0.76 to 1.24, p = 0.81). Adjusted regression analyses showed no significant differences in the risk of recurrent MI between groups (Gp1 vs Gp3, HR 0.79, CI 0.12 to 5.27, p = 0.8; Gp1 vs Gp2 HR 1.10, CI 0.25 to 4.77, p = 0.90; Gp2 vs Gp3 HR 0.58, CI 0.08 to 4.06, p = 0.58). In conclusion, in a large observational cohort of male veterans with previous MI, normalization of TT levels with TRT was associated with decreased all-cause mortality compared with those with non-normalized TT levels and the untreated group. Furthermore, in this high-risk population, TRT was not associated with an increased risk of recurrent MI.
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http://dx.doi.org/10.1016/j.amjcard.2019.07.019DOI Listing
October 2019

Environmental Tobacco Smoke and Cardiovascular Disease.

Int J Environ Res Public Health 2018 12 31;16(1). Epub 2018 Dec 31.

Division of Cardiovascular Medicine, University of California San Francisco, Fresno, CA 93701, USA.

Environmental tobacco smoke (ETS) and its sequelae are among the largest economic and healthcare burdens in the United States and worldwide. The relationship between active smoking and atherosclerosis is well-described in the literature. However, the specific mechanisms by which ETS influences atherosclerosis are incompletely understood. In this paper, we highlight the definition and chemical constituents of ETS, review the existing literature outlining the effects of ETS on atherogenesis and thrombosis in both animal and human models, and briefly outline the public health implications of ETS based on these data.
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http://dx.doi.org/10.3390/ijerph16010096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339042PMC
December 2018

Normalization of Testosterone Levels After Testosterone Replacement Therapy Is Not Associated With Reduced Myocardial Infarction in Smokers.

Mayo Clin Proc Innov Qual Outcomes 2017 Jul 18;1(1):57-66. Epub 2017 May 18.

Division of Cardiovascular Research, Kansas City VA Medical Center, Kansas City, MO.

Objective: To examine the effect of cigarette smoking (CS) status and total testosterone (TT) levels after testosterone replacement therapy (TRT) on all-cause mortality, myocardial infarction (MI), and stroke in male smokers and nonsmokers without history of MI and stroke.

Participants And Methods: Data from 18,055 males with known CS status and low TT levels who received TRT at the Veterans Health Administration between December 1, 1999, and May 31, 2014, were grouped into (1) current smokers with normalized TT, (2) current smokers with nonnormalized TT, (3) nonsmokers with normalized TT, and (4) nonsmokers with nonnormalized TT. Combined effect of CS status and TT level normalization after TRT on all-cause mortality, MI, and stroke was compared using propensity score-weighted Cox proportional hazard models.

Results: Normalization of serum TT levels in nonsmokers was associated with a significant decrease in all-cause mortality (hazard ratio [HR]=0.526; 95% CI, 0.477-0.581; <.001) and MI (HR=0.717; 95% CI, 0.522-0.986; <.001). Among current smokers, normalization of serum TT levels was associated with a significant decrease in only all-cause mortality (HR=0.563; 95% CI, 0.488-0.649; <.001) without benefit in MI (HR=1.096; 95% CI, 0.698-1.720; =.69). Importantly, compared with nonsmokers with normalized TT, all-cause mortality (HR=1.242; 95% CI, 1.104-1.396; <.001), MI (HR=1.706; 95% CI, 1.242-2.342; =.001), and stroke (HR=1.590; 95% CI, 1.013-2.495; =.04) were significantly higher in current smokers with normalized TT.

Conclusion: We conclude that active CS may negate the protective effect of testosterone level normalization on all-cause mortality and MI after TRT.
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http://dx.doi.org/10.1016/j.mayocpiqo.2017.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135014PMC
July 2017

Normalization of Testosterone Levels After Testosterone Replacement Therapy Is Associated With Decreased Incidence of Atrial Fibrillation.

J Am Heart Assoc 2017 May 9;6(5). Epub 2017 May 9.

Division of Cardiovascular Medicine, Kansas City VA Medical Center, Kansas City, MO

Background: Atrial fibrillation (AF) is the most common cardiac dysrhythmia associated with significant morbidity and mortality. Several small studies have reported that low serum total testosterone (TT) levels were associated with a higher incidence of AF. In contrast, it is also reported that anabolic steroid use is associated with an increase in the risk of AF. To date, no study has explored the effect of testosterone normalization on new incidence of AF after testosterone replacement therapy (TRT) in patients with low testosterone.

Methods And Results: Using data from the Veterans Administrations Corporate Data Warehouse, we identified a national cohort of 76 639 veterans with low TT levels and divided them into 3 groups. Group 1 had TRT resulting in normalization of TT levels (normalized TRT), group 2 had TRT without normalization of TT levels (nonnormalized TRT), and group 3 did not receive TRT (no TRT). Propensity score-weighted stabilized inverse probability of treatment weighting Cox proportional hazard methods were used for analysis of the data from these groups to determine the association between post-TRT levels of TT and the incidence of AF. Group 1 (40 856 patients, median age 66 years) had significantly lower risk of AF than group 2 (23 939 patients, median age 65 years; hazard ratio 0.90, 95% CI 0.81-0.99, =0.0255) and group 3 (11 853 patients, median age 67 years; hazard ratio 0.79, 95% CI 0.70-0.89, =0.0001). There was no statistical difference between groups 2 and 3 (hazard ratio 0.89, 95% CI 0.78- 1.0009, =0.0675) in incidence of AF.

Conclusions: These novel results suggest that normalization of TT levels after TRT is associated with a significant decrease in the incidence of AF.
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http://dx.doi.org/10.1161/JAHA.116.004880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524065PMC
May 2017

Association Between Testosterone Replacement Therapy and the Incidence of DVT and Pulmonary Embolism: A Retrospective Cohort Study of the Veterans Administration Database.

Chest 2016 09 12;150(3):563-71. Epub 2016 May 12.

Division of Cardiovascular Diseases, University of Kansas Medical Center, Kansas City, KS. Electronic address:

Background: Testosterone replacement therapy (TRT) prescriptions have increased several-fold in the last decade. There have been concerns regarding a possible increased incidence of DVT and pulmonary embolism (PE) with TRT. Few data support the association between TRT and DVT/PE. We evaluated the incidence of DVT and PE in men who were prescribed TRT for low serum total testosterone (sTT) levels.

Methods: This is a retrospective cohort study, conducted using data obtained from the Veterans Affairs Informatics and Computing Infrastructure. We compared the incidence of DVT/PE between those who received TRT and subsequently had normal on-treatment sTT levels (Gp1), those who received TRT but continued to have low on-treatment sTT (Gp2), and those who did not receive TRT (Gp3). Those with prior history of DVT/PE, cancer, hypercoagulable state, and chronic anticoagulation were excluded.

Results: The final cohort consisted of 71,407 subjects with low baseline sTT. Of these, 10,854 did not receive TRT (Gp3) and 60,553 received TRT. Of those who received TRT, 38,362 achieved normal sTT (Gp1) while 22,191 continued to have low sTT (Gp2). The incidence of DVT/PE was 0.5%, 0.4%, and 0.4% in Gp1, Gp2, and Gp3, respectively. Univariate, multivariate, and stabilized inverse probability of treatment weights analyses showed no statistically significant difference in DVT/PE-free survival between the various groups.

Conclusions: This study did not detect a significant association between testosterone replacement therapy and risk of DVT/PE in adult men with low sTT who were at low to moderate baseline risk of DVT/PE.
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http://dx.doi.org/10.1016/j.chest.2016.05.007DOI Listing
September 2016

Cigarette Smoke Amplifies Inflammatory Response and Atherosclerosis Progression Through Activation of the H1R-TLR2/4-COX2 Axis.

Front Immunol 2015 9;6:572. Epub 2015 Nov 9.

Department of Medicine, Division of Allergy, Clinical Immunology and Rheumatology, University of Kansas Medical Center , Kansas City, KS , USA.

Emerging evidence suggests that infection and persistent inflammation are key players in the pathogenesis of atherosclerotic cardiovascular disease (CVD). Although it is well established that cigarette smoke (CS) promotes atherosclerotic CVD, very little is known about the potential impact of the collective effects of CS and intermittent or chronic subclinical infection on atherosclerosis. Our previous studies demonstrated that mast cell-derived histamine and lipopolysaccharide (LPS) synergistically enhance endothelial cell inflammatory response. We further noted that the synergy between histamine and LPS was due to reciprocal upregulation of histamine receptor and Toll-like receptor 4 (TLR4) expression and functions. These results suggest that the combined and persistent effects of mast cell mediators and bacterial agents on the vasculature are risk factors of CVD. Our recent data demonstrated that CS extract enhances histamine- and LPS-induced expression of cyclooxygenase-2 (COX-2) in endothelial cells, suggesting that CS and mast cell mediators may collectively amplify inflammatory response in the vessel wall. We hypothesize that CS enhances histamine-mediated upregulation of TLR2/TLR4 signaling in the endothelium and promotes progression of atherosclerosis. This article presents our perspective on the modulatory effects of CS and nicotine on the "histamine-TLR-COX-2 axis."
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http://dx.doi.org/10.3389/fimmu.2015.00572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4638143PMC
November 2015

Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men.

Eur Heart J 2015 Oct 6;36(40):2706-15. Epub 2015 Aug 6.

Division of Cardiovascular Research, Kansas City VA Medical Center, Kansas City, MO, USA Division of Cardiovascular Diseases, University of Kansas Medical Center, Kansas City, KS, USA Division of Cardiovascular Medicine, Kansas City VA Medical Center, 4801 E. Linwood Boulevard, Kansas City, MO 64128, USA

Aims: There is a significant uncertainty regarding the effect of testosterone replacement therapy (TRT) on cardiovascular (CV) outcomes including myocardial infarction (MI) and stroke. The aim of this study was to examine the relationship between normalization of total testosterone (TT) after TRT and CV events as well as all-cause mortality in patients without previous history of MI and stroke.

Methods And Results: We retrospectively examined 83 010 male veterans with documented low TT levels. The subjects were categorized into (Gp1: TRT with resulting normalization of TT levels), (Gp2: TRT without normalization of TT levels) and (Gp3: Did not receive TRT). By utilizing propensity score-weighted Cox proportional hazard models, the association of TRT with all-cause mortality, MI, stroke, and a composite endpoint was compared between these groups. The all-cause mortality [hazard ratio (HR): 0.44, confidence interval (CI) 0.42-0.46], risk of MI (HR: 0.76, CI 0.63-0.93), and stroke (HR: 0.64, CI 0.43-0.96) were significantly lower in Gp1 (n = 43 931, median age = 66 years, mean follow-up = 6.2 years) vs. Gp3 (n = 13 378, median age = 66 years, mean follow-up = 4.7 years) in propensity-matched cohort. Similarly, the all-cause mortality (HR: 0.53, CI 0.50-0.55), risk of MI (HR: 0.82, CI 0.71-0.95), and stroke (HR: 0.70, CI 0.51-0.96) were significantly lower in Gp1 vs. Gp2 (n = 25 701, median age = 66 years, mean follow-up = 4.6 years). There was no difference in MI or stroke risk between Gp2 and Gp3.

Conclusion: In this large observational cohort with extended follow-up, normalization of TT levels after TRT was associated with a significant reduction in all-cause mortality, MI, and stroke.
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http://dx.doi.org/10.1093/eurheartj/ehv346DOI Listing
October 2015

Mechanisms of coronary thrombosis in cigarette smoke exposure.

Arterioscler Thromb Vasc Biol 2013 Jul 16;33(7):1460-7. Epub 2013 May 16.

Department of Medicine, Division of Cardiology, University of Kansas School of Medicine, KS 93721, USA.

Acute rupture or erosion of a coronary atheromatous plaque and subsequent coronary artery thrombosis cause the majority of sudden cardiac deaths and myocardial infarctions. Cigarette smoking is a major risk factor for acute coronary thrombosis. Indeed, a majority of sudden cardiac deaths attributable to acute thrombosis are in cigarette smokers. Both active and passive cigarette smoke exposure seem to increase the risk of coronary thrombosis and myocardial infarctions. Cigarette smoke exposure seems to alter the hemostatic process via multiple mechanisms, which include alteration of the function of endothelial cells, platelets, fibrinogen, and coagulation factors. This creates an imbalance of antithrombotic/prothrombotic factors and profibrinolytic/antifibrinolytic factors that support the initiation and propagation of thrombosis.
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http://dx.doi.org/10.1161/ATVBAHA.112.300154DOI Listing
July 2013

Acute cigarette smoke exposure reduces clot lysis--association between altered fibrin architecture and the response to t-PA.

Thromb Res 2010 Nov 1;126(5):426-30. Epub 2010 Sep 1.

Division of Cardiovascular Medicine, University of California San Francisco, Fresno, CA 93721, USA.

Background: Enhanced thrombolysis is a proposed mechanism for reduced mortality in cigarette smokers with STEMI ("smoker's paradox"). The mechanisms remain unclear but studies suggest fibrin architecture (FA) may affect thrombolysis. Our group has previously shown that acute cigarette smoke exposure (CSE) alters FA. This study was done to evaluate the association between FA, thrombolysis and CSE.

Methods And Results: Otherwise healthy smokers (n=22) were studied before and after smoking two cigarettes. Non-smokers (n=22) served as controls. Two ex-vivo models were used to evaluate clot lysis of venous blood and these data were compared to FA as determined by SEM. In the first model, clot lysis in a glass tube at 60minutes after addition of t-PA was measured. The second model quantified lysis utilizing thromboelastography. With the latter, after a clot reached maximum strength, t-PA was added and clot lysis at 60min was noted. SEM studies were performed on platelet poor plasma mixed with thrombin and FA was examined at 20K. Clot lysis was similar in both groups except that post-smoking, TEG showed a significantly lower lysis compared to pre- and non-smoking clots. SEM analysis showed significantly thinner fibers and denser clots post-smoking.

Conclusions: Venous clots from smokers failed to show an enhanced lysis when exposed to t-PA. In fact, acute CSE was associated with changes in FA and increased resistance to thrombolysis. These findings in part may explain enhanced thrombogenicity but suggest that mechanisms other than enhanced fibrinolysis are likely to be responsible for "smoker's paradox."
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http://dx.doi.org/10.1016/j.thromres.2010.07.021DOI Listing
November 2010

Effects of cigarette smoke exposure on clot dynamics and fibrin structure: an ex vivo investigation.

Arterioscler Thromb Vasc Biol 2010 Jan 8;30(1):75-9. Epub 2009 Oct 8.

Division of Cardiovascular Medicine, University of California San Francisco, Fresno, 2823 N Fresno Street, Fresno, CA 93721, USA.

Objective: The purpose of this study was to examine the effect of cigarette smoke exposure (CSE) on clot dynamics and fibrin architecture and to isolate the relative contribution of platelets and fibrinogen to clot dynamics.

Methods And Results: From young healthy males smokers (n=34) and nonsmokers (n=34) a baseline blood was drawn, and smokers had another blood draw after smoking 2 regular cigarettes. Using thromboelastography (TEG) the degree of platelet-fibrin interaction was measured. In additional experiments, abciximab (20 microg/mL) was added to the smokers samples (n=27) to reduce the effects of platelet function from the TEG parameters. The maximum clot strength (G) obtained with abciximab measured mainly the contribution of fibrinogen to clot strength (GF). By subtracting GF from G, the contribution of platelets to clot strength (GP) was presumed. A significant difference was found for all TEG parameters between nonsmokers versus postsmoking and pre- versus postsmoking samples. Postsmoking both GF and GP were significantly higher as compared to presmoking. On electron microscopy and turbidity analysis, postsmoking fibrin clots were significantly different compared to presmoking and nonsmoking samples.

Conclusions: Acute CSE changes clot dynamics and alters fibrin architecture. Both functional changes in fibrinogen and platelets appear to contribute to heightened thrombogenicity after acute CSE.
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http://dx.doi.org/10.1161/ATVBAHA.109.195024DOI Listing
January 2010

Frequency of elevated troponin I and diagnosis of acute myocardial infarction.

Am J Cardiol 2009 Jul 4;104(1):9-13. Epub 2009 May 4.

Division of Cardiology, UCSF Fresno Medical Education Program, Fresno, CA, USA.

This study evaluated the incidence and type of acute myocardial infarction (AMI) in a consecutive population with increased troponin I (TnI). AMI has recently been redefined and subclassified. Incidence, demographic data, angiographic findings, and hospital mortality of patients with various AMI subtypes or an increased TnI in the absence of AMI have not been previously reported in a prospective study. Over a 3-month period, all patients admitted from an emergency room or from in-patient services with >1 TnI level >0.04 ng/ml were evaluated and subclassified in AMI subgroups. In-hospital or recent coronary angiograms were reviewed. In-hospital mortality was noted. Of 2,944 patients with serial TnI measurements, 728 had an increased TnI and 701 (23.8%) were evaluated. Two hundred sixteen (30.8% with increased TnI and 42.7% with "rule-out MI" on admission) met criteria for AMI. One hundred forty-three (20.4%) had type 1, 64 (9.1%) had type 2, whereas 461 (65.8%) did not meet criteria for AMI. On multivariate analysis, use of angiography, peak TnI level, hyperlipidemia, and illicit drug use were independently associated with the diagnosis of AMI. TnI of 0.28 ng/ml had a 70% sensitivity and specificity for AMI diagnosis. In conclusion, a minority admitted with increased TnI have AMI by the universal definition. Type 1 is the most common AMI and is associated with higher TnI values and these patients are more likely to undergo angiography. Type 2 AMI is often associated with illicit drug use.
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http://dx.doi.org/10.1016/j.amjcard.2009.03.003DOI Listing
July 2009

The pathophysiology of cigarette smoking and cardiovascular disease: an update.

J Am Coll Cardiol 2004 May;43(10):1731-7

Comprehensive Cardiovascular Center, Saint Vincent Catholic Medical Centers of New York, New York, New York 10011, USA.

Cigarette smoking (CS) continues to be a major health hazard, and it contributes significantly to cardiovascular morbidity and mortality. Cigarette smoking impacts all phases of atherosclerosis from endothelial dysfunction to acute clinical events, the latter being largely thrombotic. Both active and passive (environmental) cigarette smoke exposure predispose to cardiovascular events. Whether there is a distinct direct dose-dependent correlation between cigarette smoke exposure and risk is debatable, as some recent experimental clinical studies have shown a non-linear relation to cigarette smoke exposure. The exact toxic components of cigarette smoke and the mechanisms involved in CS-related cardiovascular dysfunction are largely unknown, but CS increases inflammation, thrombosis, and oxidation of low-density lipoprotein cholesterol. Recent experimental and clinical data support the hypothesis that cigarette smoke exposure increases oxidative stress as a potential mechanism for initiating cardiovascular dysfunction.
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http://dx.doi.org/10.1016/j.jacc.2003.12.047DOI Listing
May 2004

Predictors of troponin elevation after percutaneous coronary intervention.

Am J Cardiol 2004 Mar;93(6):747-50

Comprehensive Cardiovascular Center, St. Vincent Catholic Medical Centers of New York, New York, New York 10011, USA.

The predictors of troponin release after percutaneous coronary intervention were prospectively assessed in 405 consecutive patients. Troponin release occurred frequently (27%) and was associated with complications during the procedure, including sapheneous vein graft interventions, multistent use, glycoprotein IIb/IIIa use, and a history of hypercholesterolemia.
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http://dx.doi.org/10.1016/j.amjcard.2003.11.070DOI Listing
March 2004

Reactive oxygen species are involved in smoking-induced dysfunction of nitric oxide biosynthesis and upregulation of endothelial nitric oxide synthase: an in vitro demonstration in human coronary artery endothelial cells.

Circulation 2003 May 21;107(18):2342-7. Epub 2003 Apr 21.

Saint Vincent Catholic Medical Centers of New York, New York 10011, USA.

Background: Our group has previously shown that human umbilical vein endothelial cells exposed to smokers' serum decreased nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) activity in the presence of increased eNOS expression. In the present study, we examined whether these observations extended to human coronary artery endothelial cells (HCAECs). In addition, the role of reactive oxygen species in the observed alterations was examined.

Methods And Results: HCAECs were incubated with serum from 10 nonsmokers and 15 smokers for 12 hours with or without the addition of either polyethylene glycol-superoxide dismutase (PEG-SOD, 300 U/mL), PEG-SOD+PEG-catalase (1000 U/mL), chelerythrine (3 micromol/L), or tetrahydrobiopterin (20 micromol/L). At the end of incubation, NO, eNOS protein, and eNOS activity were measured from the same culture. HCAECs incubated with smokers' serum alone showed significantly lower NO production (P<0.05) and eNOS activity (P<0.005) but higher eNOS expression (P<0.005) compared with nonsmokers. In smokers, addition of PEG-SOD, PEG-SOD+PEG-catalase, or tetrahydrobiopterin significantly (P<0.05) improved NO levels and eNOS activity. Interestingly, in the same smokers, a significant decrease in eNOS expression was only seen with the addition of PEG-SOD+PEG-catalase (P<0.05) and treatment with PEG-SOD alone insignificantly increased eNOS expression.

Conclusions: The present study indicates that in vitro, HCAECs show similar changes in NO biosynthesis as human umbilical vein endothelial cells when exposed to smokers' serum and also confirms that oxidative stress plays a central role in smoking-mediated dysfunction of NO biosynthesis in endothelial cells. Furthermore, these data support other studies suggesting a role for hydrogen peroxide in the upregulation of eNOS.
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http://dx.doi.org/10.1161/01.CIR.0000066691.52789.BEDOI Listing
May 2003

Impaired mitochondrial function induced by serum from septic shock patients is attenuated by inhibition of nitric oxide synthase and poly(ADP-ribose) synthase.

Crit Care Med 2003 Feb;31(2):353-8

Saint Vincent's Catholic Medical Centers of New York, New York Medical College, Valhalla, USA.

Objective: The purpose of this study was to determine the role of nitric oxide and poly(ADP-ribose) synthase on impaired mitochondrial function in septic shock.

Design: Human umbilical vein endothelial cells were incubated with serum from ten healthy controls, 20 patients with septic shock, and seven critically ill patients who were not septic. The experiment was repeated after pretreatment with 3-aminobenzamide, a poly(ADP-ribose) synthase inhibitor, or N(G)-methyl-L-arginine, a nonspecific nitric oxide synthase inhibitor.

Measurements: Mitochondrial respiration was measured using a modified MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) assay.

Setting: Research laboratory.

Main Result: Endothelial cell mitochondrial respiration was significantly depressed by septic serum and averaged 61% +/- 6% of control values (p <.05). Incubation with septic serum as compared with control serum also significantly decreased cellular adenosine triphosphate levels (6.7 +/- 1.2 nM vs. 13.5 +/- 1.9 nM, p<.01). The level of mitochondrial respiration in endothelial cells exposed to septic serum did not correlate with arterial lactate concentration but was correlated with both cardiac output (r(s) =.52, p<.05) and mixed venous oxygen saturation (r(s) =.61, p<.05). Pretreatment with N(G)-methyl-L-arginine significantly increased mitochondrial respiration in endothelial cells treated with septic serum from 63% +/- 6% of normal to 88% +/- 6% (p <.05) of normal values. Similarly, pretreatment with 3-aminobenzamide increased mitochondrial respiration in endothelial cells treated with septic serum from 64% +/- 6% to 100% +/- 4% (p <.01) of normal values. Endothelial cells incubated with serum from nonseptic critically ill patients did not demonstrate a significant decrease in mitochondrial respiration.

Conclusion: In vitro mitochondrial respiration was significantly depressed by septic serum. The addition of N(G)-methyl-L-arginine, a nitric oxide synthase inhibitor, and 3-aminobenzamide, a blocker of the poly(ADP-ribose) synthase pathway, significantly attenuated this suppression. These data suggest that nitric oxide and poly(ADP-ribose) synthase activation may play an important role in the inhibition of mitochondrial respiration in septic shock.
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http://dx.doi.org/10.1097/01.CCM.0000050074.82486.B2DOI Listing
February 2003

Peripheral conduction disease in left ventricular dysfunction.

Am J Cardiol 2003 Feb;91(3):354-6

Department of Medicine, The Comprehensive Cardiovascular Center, Saint Vincent Catholic Medical Centers of New York, New York, New York, USA.

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http://dx.doi.org/10.1016/s0002-9149(02)03170-3DOI Listing
February 2003

Acute coronary lesions and troponin elevation in unstable angina pectoris or non-ST elevation acute myocardial infarction.

Am J Cardiol 2002 Oct;90(7):770-3

Department of Medicine, The Comprehensive Cardiovascular Center, Saint Vincent Catholic Medical Centers of New York, New York 10011, USA.

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http://dx.doi.org/10.1016/s0002-9149(02)02609-7DOI Listing
October 2002

Smoking is associated with altered endothelial-derived fibrinolytic and antithrombotic factors: an in vitro demonstration.

Circulation 2002 Aug;106(8):905-8

Saint Vincent Catholic Medical Centers of New York, New York, NY 10011, USA.

Background: Data about the effects of smoking on thrombo-hemostatic factors (tissue factor [TF] and tissue factor pathway inhibitor [TFPI-1]) are limited and on fibrinolytic factors (tissue plasminogen activator [t-PA] and plasminogen activator inhibitor-1 [PAI-1]) are debatable. The present study investigated the smoking-related, endothelial cell (EC)-specific responses for these factors and their relation to nitric oxide (NO) production in vitro.

Methods And Results: Serum from 8 nonsmokers and 15 smokers were incubated with confluent (approximately 85%) human umbilical vein endothelial cells (HUVECs) in 24-well tissue-culture plates for 12 hours. After the incubation, basal NO, t-PA, PAI-1, TF, TFPI-1 production, and substance P (SP)-stimulated NO, t-PA, and PAI-1 production were determined. HUVECs treated with smokers' serum showed lower basal (P<0.02) and SP-stimulated (P=0.059) t-PA production but similar basal and stimulated PAI-1 production (P=0.9 and P=0.6) compared with nonsmokers. Basal t-PA/PAI-1 molar ratio was significantly reduced in smokers (P<0.005). TFPI-1 level in the cell culture supernatant was also significantly lower in smokers compared with the nonsmoker group (P<0.05) with no difference in TF level between both groups (P=0.5). As previously reported, both basal (P<0.001) and SP-stimulated (P<0.05) NO production were significantly reduced in smokers. Basal TFPI-1 in culture correlated positively with basal NO production (r=0.42, P=0.04) and negatively with serum cotinine level (r=-0.6, P=0.01).

Conclusions: These results indicate that cigarette smoking is associated with alterations in EC-derived fibrinolytic (t-PA) and antithrombotic (TFPI-1) factors. To our knowledge, this is the first demonstration that EC-derived TFPI is affected by smoking and endogenous NO or that the degree of smoke exposure may influence TFPI levels in an EC milieu.
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http://dx.doi.org/10.1161/01.cir.0000029091.61707.6bDOI Listing
August 2002

Mechanisms of platelet-neutrophil interactions and effects on cell filtration in septic shock.

Shock 2002 Jun;17(6):508-12

New York Medical College, Saint Vincent's Hospital and Medical Center, New York 10011, USA.

ABSTRACT-We examined the mechanisms and the adhesive molecules mediating platelet-neutrophil adhesion in patients with septic shock. Neutrophils, platelets, and platelet poor plasma (NPPP) were isolated from 12 normal volunteers. Platelets and neutrophils were stimulated with platelet poor plasma (SPPP) removed from 12 patients in septic shock. Cell adhesion was assessed by filtration through 5-microm pore filters and by flow cytometry. Blocking monoclonal antibodies were used against the platelet and neutrophil surface receptors glycoprotein complex IIb/IIla, P-selectin, ICAM-2, CD11a, CD11b, and CD18. The filtration pressure (Pi) of cells suspended in SPPP was significantly greater than that of cells suspended in NPPP (24 +/- 1.0 mmHg vs. 14 +/- 1.0 mmHg; P< 0.05). The difference between the Pi of cells suspended in SPPP or NPPP (deltaPi SPPP-NPPP) in the presence of monoclonal antibodies anti-CD41, anti-CD62P, abciximab, anti-CD11a, anti-CD11b, and anti-CD18 was significantly less than the APi SPPP-NPPP of cell suspensions without the addition of these monoclonal antibodies (P < 0.01). The greatest reduction in Pi occurred when platelet receptor P-selectin was blocked simultaneously with the CD11b receptor on the neutrophil as compared to all other single blocking monoclonal antibodies or combinations of monoclonal antibodies. The mean fluorescence of activated platelet CD63-PE binding to neutrophils suspended in SPPP was significantly greater than that of cells suspended in NPPP (780 +/- 130 Ifu vs. 295 +/- 35 Ifu; P < 0.05). The greatest attenuation in mean fluorescence occurred by blocking the P-selectin receptor on the platelet simultaneously with CD11b receptor on the neutrophil. We conclude that platelet-neutrophil aggregation is increased in septic shock. This aggregation is mediated by the interaction of multiple platelet and neutrophil surface receptors. The platelet receptor P-selectin and the neutrophil receptor CD11b/CD18 appear to play the most important role in these interactions.
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http://dx.doi.org/10.1097/00024382-200206000-00012DOI Listing
June 2002

Heavy and light cigarette smokers have similar dysfunction of endothelial vasoregulatory activity: an in vivo and in vitro correlation.

J Am Coll Cardiol 2002 Jun;39(11):1758-63

Department of Medicine, the Comprehensive Cardiovascular Center, Saint Vincent Catholic Medical Centers of New York, 170 West 12th Street, New York, NY 10011, USA.

Objectives: The goal of this study was to investigate the dose-dependent effects of active cigarette smoking on endothelial nitric oxide (NO) and endothelin-1 (ET-1) biosynthesis.

Background: Limited studies have suggested that active cigarette smoking may be associated with a dose-dependent reduction of endothelium-dependent vasodilation (EDV). The underlying biochemical changes that cause this dose-specific effect, such as changes in the endothelial NO biosynthetic pathway and ET-1 production, have not been examined.

Methods: Flow- and nitroglycerin-mediated reactivity of the brachial artery were measured in eight nonsmokers, seven light smokers (< or =1 pack/week) and eight heavy smokers (> or =1 pack/day), and their sera were added to confluent ( approximately 85%) monolayers of human umbilical endothelial cells (HUVECs) for 12 h. Basal and substance P-stimulated NO and basal ET-1 production were measured. The HUVECs used for measuring basal NO production were lysed, and both endothelial NO synthase (eNOS) protein expression and eNOS activity were determined.

Results: Serum cotinine level and pack-years of smoking were significantly lower in light smokers compared with heavy smokers (p < 0.006 and p < 0.004, respectively). There were no significant differences between heavy smokers and light smokers in EDV (p = 0.52), basal- (p = 0.70) and stimulated-NO production (p = 0.95), eNOS protein (p = 0.40) and eNOS activity (p = 0.63). Compared with nonsmokers, all the parameters were significantly altered in both of the smokers' groups. No differences were found in nitroglycerin-mediated vasodilation and in vitro ET-1 production among the three groups.

Conclusions: These results indicate light smoking may have similar detrimental effects on EDV and NO biosynthetic pathway as does heavy smoking. These data may have important implications concerning the amount of active cigarette exposure that imparts cardiovascular risk.
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http://dx.doi.org/10.1016/s0735-1097(02)01859-4DOI Listing
June 2002
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