ABSTRACT Purpose: In patients with Takotsubo cardiomyopathy (TTC), left ventricular wall motion (LVWM) usually recovers rapidly, therefore residual symptoms may be described to depression. However, we have previously shown that... more
ABSTRACT Purpose: In patients with Takotsubo cardiomyopathy (TTC), left ventricular wall motion (LVWM) usually recovers rapidly, therefore residual symptoms may be described to depression. However, we have previously shown that inflammatory activation and accentuated BNP release persist for at least 3 months post TTC, and this is associated with impaired global longitudinal strain (GLS). We have now sought to determine (1) the bases for heterogeneity of residual GLS and (2) whether this results either from severe acute inflammation or slow resolution of inflammatory changes. Methods: Data from TTC patients with adequate 2D speckle-tracking echocardiographs were evaluated. Correlations between GLS and (i) severity of acute episode [peak CK, NT-proBNP, metanephrine, high sensitive C-reactive protein (hsCRP), asymmetric dimethylarginine (ADMA) levels, platelet responsiveness to NO, LVWM score index, and myocardial T2 signal intensity on MRI], (ii) residual markers of inflammation were evaluated by univariate and multiple linear regression analyses. Results: In 51 TTC patients aged 66±12 (SD), acute GLS was significantly impaired compared to 3 months (-12±4% vs -18±3%, p=0.0001). GLS at 3 months was significantly correlated with acute elevation of NT-proBNP and metanephrine levels (r=0.34, p=0.02; r=0.4, p=0.009, respectively). Moreover, metanephrine levels represented an independent predictor of poor recovery (β=0.4; p=0.03). Furthermore, residual GLS was significantly correlated with simultaneous NT-proBNP (r=0.47, p=0.003); this association persisted with multiple linear regression (β=0.51; p=0.002).
and Hypotheses: The signal transduction pathway modulated by activation or blockade of platelet P2Y12 receptors is linked to PGE1-stimulated adenylate cyclase effects, but this link's impact on... more
and Hypotheses: The signal transduction pathway modulated by activation or blockade of platelet P2Y12 receptors is linked to PGE1-stimulated adenylate cyclase effects, but this link's impact on P2Y12 receptor antagonist response is uncertain. We therefore tested the hypothesis that pre-treatment platelet responsiveness to PGE1 predicts subsequent responsiveness to clopidogrel. In order to maximise heterogeneity of platelet responsiveness to PGE1 we investigated both healthy subjects (n=30) and patients with CHD undergoing elective coronary stenting (n=22), all genotyped for common CYP2C19 variants associated with clopidogrel sensitivity (CS). We determined baseline pre-clopidogrel platelet sensitivity to the inhibitory effects of PGE1 by ADP-induced whole blood aggregation. Clopidogrel was administered for 7days utilising a weight-based regimen. CS was expressed as change (Δ) in ADP-induced aggregation and in VASP-phosphorylation (VASP-P). We used univariate and multivariate analysis to correlate such parameters with PGE1 sensitivity, BMI and presence/absence of CHD. In the study cohort, pre-treatment responsiveness to PGE1 varied widely (70±28 [standard deviation (SD)]% inhibition of aggregation: range 10 to 100%). In the entire study cohort, pre-treatment PGE1 sensitivity correlated with CS irrespective of genotype. On univariate analysis, CS was not significantly greater for patients without than those with loss-of-function mutations. Moreover, at multivariate analysis, PGE1 sensitivity, but not genotype, was a strong correlate of ΔADP and ΔVASP-P (P<0.0001 for both). The integrity of the cAMP pathway is a major determinant of subacute CS.
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The effects of native and oxidized low density lipoproteins on platelet aggregability remain controversial despite numerous studies. In the current investigation, effects of native, minimally and extensively copper-modified low-density... more
The effects of native and oxidized low density lipoproteins on platelet aggregability remain controversial despite numerous studies. In the current investigation, effects of native, minimally and extensively copper-modified low-density lipoproteins on aggregation responses to ADP and collagen in platelet-rich plasma, washed platelets, and whole blood were studied. Preincubation with native and oxidized low-density lipoproteins (1.5-23.2 malondialdehyde equivalents [MDAeq]/mg low density lipoprotein) did not modify aggregability in platelet-rich plasma or washed platelets but increased aggregation markedly in whole blood (40-58%, p<0.01). In whole blood, the increase in response to ADP was not affected by the degree of low-density lipoprotein oxidation. This comprehensive investigation of low density lipoprotein effects on platelet aggregation therefore has demonstrated that low density lipoproteins indirectly increase platelet aggregability in whole blood, but not in platelet-ric...
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Previous studies in non-human blood vessels and in platelets have demonstrated that under hypoxic conditions release of NO from nitrite (NO2(-)) is potentiated by deoxyhaemoglobin. In the current study, we characterized hypoxic... more
Previous studies in non-human blood vessels and in platelets have demonstrated that under hypoxic conditions release of NO from nitrite (NO2(-)) is potentiated by deoxyhaemoglobin. In the current study, we characterized hypoxic potentiation of NO2(-) effects in human vasculature and platelets in vitro, addressing underlying mechanisms. The vasodilator efficacy of NO2(-), in comparison with glyceryl trinitrate (GTN), was evaluated in vitro, using segments of human saphenous vein. Under hypoxic conditions, there was a leftward shift of the NO2(-) concentration-response curve (EC50: 22 μM in hyperoxia vs 3.5 μM in hypoxia; p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01), but no significant potentiation of GTN effect. In the presence of red blood cells, hypoxic potentiation of NO2(-) vasodilator effect was accentuated. In whole blood samples and platelet-rich plasma (PRP) we assessed inhibition of platelet aggregation by NO2(-) (1mM), in comparison with that of sodium nitroprusside (SNP, 10 μM). In individual subjects (n=37), there was a strong correlation (r=0.75, p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001) between anti-aggregatory effects of NO2(-) and SNP in whole blood, signifying that resultant sGC activation underlies biological effect and responses to NO2(-) are diminished in the presence of NO resistance. In PRP, the effects of NO2(-) were less pronounced than in whole blood (p=0.0001), suggesting an important role of Hb (within RBCs) in the bioconversion of NO2(-) to NO. Inhibition of platelet aggregation by NO2(-) was almost 3-fold greater in venous than in arterial blood (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001), and deoxyHb concentration directly correlated (r=0.69, p=0.013) with anti-aggregatory response. Incremental hypoxia applied to venous blood samples (in hypoxic chamber) caused a progressive increase in both deoxyHb level and anti-aggregatory effect of NO2(-). When subjects inhaled a 12% O2 mixture for 20 min, there was a 3-fold rise in blood deoxyHb fraction (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01). In PRP, response to NO2(-) also increased under hypoxia, and was further enhanced (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01) by deoxyHb. Furthermore, deoxyHb exerted significant anti-aggregatory effects even in the absence of added NO2(-), suggesting a role for endogenous NO2(-). The results of this work provide further mechanistic insights into hypoxic potentiation of vasodilator and anti-aggregatory actions of NO2(-). In human saphenous veins and blood, the balance of evidence suggests differential rates of NO release from NO2(-) (largely modulated by deoxyHb) as the fundamental mechanism.
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Research Interests:
Hyperglycemia in patients with acute coronary syndromes is associated with poor outcomes, and its rapid correction with insulin infusion has been shown to restore platelet responsiveness to nitric oxide (NO) and to suppress superoxide... more
Hyperglycemia in patients with acute coronary syndromes is associated with poor outcomes, and its rapid correction with insulin infusion has been shown to restore platelet responsiveness to nitric oxide (NO) and to suppress superoxide (O2(-)) generation. Thioredoxin-interacting protein (TXNIP) has recently emerged as a pivotal modulator of hyperglycemia-induced inflammation, O2(-) production and impairment of NO signaling, but it is not known whether its expression in platelets can be rapidly down-regulated. In twelve hyperglycemic acute coronary syndrome patients, we evaluated the putative role of TXNIP suppression in the platelet NO response after reversal of hyperglycemia with insulin infusion. Insulin infusion for 13 ± 0.8 (SEM) hours decreased blood sugar level from 16.6 ± 1.6 to 8.7 ± 1.4 mmol/L (p=0.002). This induced: (1) sensitization of anti-aggregatory response to NO (from 6.5 ± 7.7 to 39.7 ± 7.0 %, p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001). (2) improved endothelial progenitor cell (EPC) function (from median 45 to 180 colony-forming units, p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). (3) decreases of whole blood reactive oxygen species content (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). However, there was no significant suppression of platelet TXNIP expression (mean decrease 59AU, 95% CI -193, +74). Correction of hyperglycemia in acute coronary syndrome patients rapidly reverses oxidative stress, restoring both platelet NO responsiveness and EPC function, but this process is largely or entirely TXNIP-independent.
Research Interests: Oxidative Stress, Signal Transduction, Humans, Platelet aggregation, Hyperglycemia, and 14 moreBlood Glucose, Insulin, Reactive Oxygen Species, Nitric oxide, Female, Male, Creatine Kinase, Aged, Middle Aged, Acute Coronary Syndrome, Oral Hypoglycemic Agents, Troponin T, Endothelial Progenitor Cells, and Down-Regulation
Nitric oxide (NO) is a physiologically important modulator of both vasomotor tone and platelet aggregability. These effects of NO are predominantly mediated by cyclic... more
Nitric oxide (NO) is a physiologically important modulator of both vasomotor tone and platelet aggregability. These effects of NO are predominantly mediated by cyclic guanosine-3,&amp;amp;amp;amp;amp;amp;#39;5&amp;amp;amp;amp;amp;amp;#39;-monophosphate (cGMP) via activation of soluble guanylate cyclase. However, in patients with ischemic heart disease, platelets and coronary/peripheral arteries are hyporesponsive to the antiaggregatory and vasodilator effects of NO donors. NO resistance is also associated with a number of coronary risk factors and presents in different disease states. It correlates with conventional measures of &amp;amp;amp;amp;amp;amp;quot;endothelial dysfunction,&amp;amp;amp;amp;amp;amp;quot; and represents a multifaceted disorder, in which smooth muscle and platelet NO resistance are equally important, as sites of abnormal NO-driven physiology. NO resistance results largely from a combination of &amp;amp;amp;amp;amp;amp;quot;scavenging&amp;amp;amp;amp;amp;amp;quot; of NO by superoxide anion radical (O(2)(-)) and of (reversible) inactivation of soluble guanylate cyclase. It constitutes an impaired physiological response to endogenous NO (endothelium-derived relaxing factor, EDRF) and, as such, may contribute to the increased risk of ischemic events. Impairment in responsiveness to NO in ischemic patients implies a potential problem that those patients, in greatest need of nitrate therapy, may be least likely to respond. The prognostic impact of NO resistance at vascular and platelet levels has been demonstrated in patients with ischemic heart disease, and it has been shown that a number of agents (angiotensin-converting enzyme [ACE] inhibitors, perhexiline, insulin, and possibly statins) ameliorate this anomaly. The current review examines different aspects of the &amp;amp;amp;amp;amp;amp;quot;NO resistance&amp;amp;amp;amp;amp;amp;quot; phenomenon and discusses some related methodological issues.
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The purpose of the study was to measure platelet aggregation and fatty acid composition for pigs fed diets containing different fats/oils, and to compare platelet aggregation with empirical indices calculated from the fatty acid... more
The purpose of the study was to measure platelet aggregation and fatty acid composition for pigs fed diets containing different fats/oils, and to compare platelet aggregation with empirical indices calculated from the fatty acid compositions of the diets and platelet phospholipids, and the index of thrombogenicity of Ulbricht and Southgate [1]. Four groups of 16 pigs were fed for 70
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The study examined possible clinical determinants of platelet resistance to nitric oxide (NO) donors in patients with stable angina pectoris (SAP) and acute coronary syndromes (ACS), relative to nonischemic patients and normal subjects.... more
The study examined possible clinical determinants of platelet resistance to nitric oxide (NO) donors in patients with stable angina pectoris (SAP) and acute coronary syndromes (ACS), relative to nonischemic patients and normal subjects. We have shown previously that platelets from patients with SAP are resistant to the antiaggregating effects of nitroglycerin (NTG) and sodium nitroprusside (SNP). Extent of adenosine diphosphate (1 micromol/liter)-induced platelet aggregation (impedance aggregometry in whole blood) and inhibition of aggregation by NTG (100 micromol/liter) and SNP (10 micromol/liter) were compared in normal subjects (n = 43), nonischemic patients (those with chest pain but no fixed coronary disease, (n = 35) and patients with SAP (n = 82) or ACS (n = 153). Association of NO resistance with coronary risk factors, coronary artery disease (CAD), intensity of angina and current medication was examined by univariate and multivariate analyses. In patients with SAP and ACS as distinct from nonischemic patients and normal subjects, platelet aggregability was increased (both p &lt; 0.01), and inhibition of aggregation by NTG and SNP was decreased (both p &lt; 0.01). Multivariate analysis revealed that NO resistance occurred significantly more frequently with ACS than with SAP (odds ratio [OR] 2.3:1), and was less common among patients treated with perhexiline (OR 0.3:1) or statins (OR 0.45:1). Therapy with other antianginal drugs, extent of CAD, intensity of angina and coronary risk factors were not associated with variability in platelet responsiveness to NO donor. Patients with symptomatic ischemic heart disease, especially ACS, exhibit increased platelet aggregability and decreased platelet responsiveness to the antiaggregatory effects of NO donors. The extent of NO resistance in platelets is not correlated with coronary risk factors. Pharmacotherapy with perhexiline and/or statins may improve platelet responsiveness to NO.
Research Interests: Multivariate Analysis, Humans, Platelet aggregation, Nitric oxide, Female, and 18 moreMale, The, Enzyme, Aged, Middle Aged, Acute Coronary Syndrome, Adult, Coronary heart disease, Public health systems and services research, Angina pectoris, Ischemic Heart Disease, Coronary Artery Disease, Syndrome, Chest Pain, Adenosine Diphosphate, Nitroglycerin, Sodium Nitroprusside, and Coronary Risk Factors
The effects of nitroglycerin (NTG) on platelet aggregation are controversial. Most in vitro investigations suggest that NTG suppresses platelet aggregation only at suprapharmacologic concentrations. We investigated various aspects of the... more
The effects of nitroglycerin (NTG) on platelet aggregation are controversial. Most in vitro investigations suggest that NTG suppresses platelet aggregation only at suprapharmacologic concentrations. We investigated various aspects of the antiaggregating effects of NTG in both normal individuals and in patients with stable angina pectoris not treated with nitrates. Platelets from patients exhibited hyperresponsiveness to ADP as an inductor of aggregation. Sublingual administration to patients of NTG (300 micrograms) decreased platelet aggregability; ADP concentrations inducing 50% aggregation were 3.3 +/- 0.3 microM after NTG versus 2.1 +/- 0.1 microM before NTG (p &lt; 0.01). Consistent with previous findings, NTG was a weak inhibitor of platelet aggregation in vitro when added before induction of aggregation. When added after the beginning of aggregation, however, NTG induced both inhibition of developing aggregation and marked disaggregation at concentrations &gt; or = 10(-8) M NTG; concentration associated with 50% reversal of aggregation was 1.4 +/- 0.3 x 10(-6) M. Therefore, antiplatelet effects of NTG in vitro are demonstrable in low, clinically achievable concentrations; previously reported effects of NTG have been underestimated owing to suboptimum experimental conditions. Platelets from patients with angina pectoris were 100-fold less responsive to the cyclic GMP-increasing and disaggregating effects of NTG in vitro, which, together with increased aggregability, could imply reduced platelet sensitivity to endogenous sources of nitric oxide (NO) in vivo. The observed antiplatelet effects of NTG raise the question of its potential utility to reduce the risk of thrombotic complications in patients with ischemic heart disease.
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Research Interests: Vitamin D, Immunohistochemistry, Oxidative Stress, Echocardiography, Protein Structure and Function, and 16 moreAortic stenosis, Nitric oxide, Animals, Male, Hypercholesterolemia, Vascular endothelium, Animal Model, Endothelial dysfunction, European, Endothelial Function, Thioredoxin, Rabbits, Aorta, Aortic Valve, Pressure Gradient, and Control Group
The A-HeFT trial demonstrated incremental survival with hydralazine/isosorbide dinitrate combination in African-American patients with chronic heart failure (CHF). It has been suggested that hydralazine might enhance nitric oxide... more
The A-HeFT trial demonstrated incremental survival with hydralazine/isosorbide dinitrate combination in African-American patients with chronic heart failure (CHF). It has been suggested that hydralazine might enhance nitric oxide (NO)-mediated effects of organic nitrates by decreasing superoxide (O (2) (-) ) formation, one of the factors inducing NO resistance. We evaluated whether hydralazine therapy potentiates nitrate-induced vasodilation and inhibition of platelet aggregation by ameliorating NO resistance. Patients (n = 14) with NYHA class II-III CHF were studied in a randomised, double-blind, placebo-controlled, crossover study of the effects of hydralazine therapy (25 mg b.d., for 1 week) on physiological responsiveness to glyceryl trinitrate (GTN). Vascular response to GTN was assessed via applanation tonometry, as change in augmentation index (AIx) over time. Platelet responsiveness to GTN and sodium nitroprusside (SNP) was determined, as inhibition of ADP-induced platelet aggregation. O (2) (-) release was evaluated during aggregation via lucigenin-derived chemiluminescence. Platelet responsiveness to the NO donors GTN and SNP was impaired, denoting the presence of severe NO resistance. Hydralazine therapy decreased systolic blood pressure by 6.8 +/- 10.5 (S.D.) mmHg (p = 0.02), and caused a reduction in AIx by 15 +/- 24% (p = 0.03). However, there were no significant changes in platelet aggregability and associated O (2) (-) release, or in platelet or vascular responses to NO donor. The results of the present study do not support the assumption that hydralazine could be viewed as a &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;NO enhancer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;; there is no evidence of attenuation of NO resistance by hydralazine treatment.
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The potential reversal of platelet aggregation in vitro by nitroglycerin in low concentrations was explored using both optical aggregometry and electron microscopy. Venous blood was collected from a cohort of normal volunteers (20 men and... more
The potential reversal of platelet aggregation in vitro by nitroglycerin in low concentrations was explored using both optical aggregometry and electron microscopy. Venous blood was collected from a cohort of normal volunteers (20 men and 10 women) aged 21 to 65 years. Aggregation in platelet-rich plasma was induced by adenosine diphosphate in concentrations just sufficient to maintain a steady state of aggregation, without a spontaneous disaggregation phase (3.5 to 5 microM). Administration of nitroglycerin after the induction of aggregation caused both inhibition of the primary wave of developing aggregation and marked disaggregation. This combined effect was maximal when nitroglycerin was added at 0.5 minute after the beginning of aggregation. The observed reversal of platelet aggregation by nitroglycerin was concentration-dependent. Significant effects occurred with nitroglycerin concentrations greater than or equal to 10(-8) M. Concentration associated with 50% reversal of aggregation was 1.52 +/- 0.24 (SEM) x 10(-6) M. Electron microscopy revealed that 10(-6) M nitroglycerin induced a significant reduction in both platelet clumping and morphologic changes associated with aggregation. The results of the current study suggest a beneficial antiplatelet effect of nitroglycerin in restoring homeostasis in the face of incipient platelet aggregation. The clinical use of nitroglycerin in patients with acute ischemic syndromes may rest on this action.