Angina in the absence of obstructive coronary artery disease, sometimes referred to as cardiac syndrome X (CSX), is a debilitating condition that disproportionately affects women. More than 50% of women evaluated for angina have non-obstructive disease by cardiac catheterization, although the total numbers of women affected by CSX are unknown. Varying clinical definitions and the lack of large scale epidemiologic studies focusing on this illness have resulted in limited knowledge about its risk factors, although there appears to be an association with black race, estrogen deficiency, and insulin resistance. Contrary to prior beliefs about the benign nature of this entity, these women suffer considerable morbidity with costly economic implications that approach the lifetime costs of healthcare utilization for those with obstructive coronary disease. Two prevailing hypotheses have emerged to explain CSX: the ischemic hypothesis detailing abnormal coronary microvascular function and the non-ischemic hypothesis describing altered pain perception and myocardial hypersensitivity. Treatment strategies have focused on both of these pathways with the main goal of improving symptoms. Beta blockers provide the most convincing evidence for benefit, with other antianginals having secondary roles. Other promising pharmacologic therapies include xanthine derivatives, estrogen replacement therapy, ACE inhibitors, and statin medications, among other emerging treatment options. Neurostimulation and lifestyle factors including exercise can also be beneficial in reducing symptoms. However, managing patients with CSX can be frustrating for both patients and physicians, as there is a lack of data regarding an optimal treatment algorithm including few large-scale randomized controlled trials to clarify effective therapies. A staggering number of women undergo coronary angiography each year due to anginal symptoms, only to discover “normal” findings. It is now appreciated that these women face significantly greater morbidity than once believed, with an uncertain treatment course and high rates of medical utilization. The pathophysiology of chest pain in women without obstructive coronary disease represents a heterogeneous mix: some have cardiac chest pain that is non-ischemic, others have cardiac chest pain due to microvascular ischemia or abnormal pain sensation, and still others have chest pain of non-cardiac origin. All of these women suffer from symptoms of chest pain; however, the prognosis and therapeutic options differ widely . The folIn 1973, Kemp introduced the term cardiac syndrome X (CSX) to describe patients with exercise-induced angina and normal coronary angiograms . HoweverThe American Heart Association (AHA) has estimated that over 9 million people in the United States suffer from angina pectoris, which significantly impacts quality of life, ability to work, and costs to society . Among pSimilar to stable angina, women presenting with acute coronary syndromes are more likely to have non-obstructive CAD compared with men, with prevalence rates of approximately 20% and 10%, respectively . Angina Demographic and clinical factors associated with CSX have largely been derived from smaller mechanistic and observational studies. Reports suggest that women with CSX are older and more frequently postmenopausal , but othet al. reported that the highest rates of non-obstructive disease in those undergoing coronary angiography were found in black women compared with other ethnicities  [1). Using the CASS registry, Maynard et al. found that 67% of black women, compared to 54% of white women, had non-obstructive coronary artery disease, with similar associations found in men [et al. evaluated 654 black patients referred for coronary angiography for suspected CAD and found that 47% of the population had either completely normal angiograms or non-obstructive lesions, a higher prevalence than in their previously studied white cohort [Angina with normal coronary arteries is a more common finding among blacks compared with whites. In the NCDR registry, Shaw d in men . Matthewe cohort . Blacks While not all studies have found similar ethnic differences , most stet al. studied a cohort of 107 women with anginal symptoms, normal coronary angiograms and positive exercise stress tests [Both estrogen deficiency and hysterectomy have been associated with CSX. Rosano et al. followed anginal symptoms, 17β-estrodial (E2) levels, and fingertip hyperemic responses to brachial artery occlusion one month before and two months after hormone replacement therapy [Sarell  therapy . Women w therapy .These studies support the premise that estrogen deficiency may be an important risk factor for CSX and offer therapeutic implications for estrogen replacement therapy. Although not always differentiated in these studies, hysterectomy even without oopherectomy appears to be a risk factor for CSX for unclear reasons. Some researchers have suggested that hysterectomy causes secondary ovarian failure leading to estrogen deficiency, providing the link between hysterectomy and CSX .et al. compared 52 women with CSX to 24 healthy age-matched controls and found higher insulin levels in those with CSX [2) [Several early studies reported greater insulin resistance in those with CSX compared with reference populations -17. In twith CSX . Patient CSX [2) . WhetherUntil recently, the prognosis for angina in the absence of coronary artery disease was considered benign. This view was supported by small international observational and case-control studies beginning in the 1960s . In geneA more recent report from a registry cohort of 32,000 patients undergoing coronary angiography in British Columbia, Canada, also confirmed the relatively good prognosis in terms of hard cardiovascular outcomes in such patients. Of all patients with normal coronary angiograms, death rate and stroke rate at one year were only 1% and 0.6% respectively. Of note, a portion of these patients underwent angiography due to acute coronary syndrome, which measurably increases subsequent vascular risk .While CSX may not translate into increased cardiovascular mortality, recent reports from the WISE investigators have called attention to the considerable morbidity encountered by women with this condition , 27. In The prognosis of women with chest pain without obstructive CAD or with CSX may be adversely impacted by the presence of concomitant coronary microvascular dysfunction -31. StudCurrent statistics suggest a substantial economic burden from angina in women without obstructive disease. In the U.S. more than four million women suffer from angina, accounting for a significant proportion of current cardiovascular healthcare costs. Over 500,000 women undergo coronary angiograms annually, of which >50% will reveal non-obstructive CAD, leading to an annual excess expenditure of $280 million , 34. Thi2). Although this sum was lower than in women with single- and multi-vessel disease, it represents an underappreciated societal cost for the care of non-obstructive coronary disease with considerable economic implications .Recently, the WISE researchers performed a cost analysis for re-hospitalization, cardiac procedures, pharmaceuticals, and cardiac complications for 883 women referred to angiography for ischemic symptoms [Two prevailing hypotheses have emerged to explain CSX and have been reviewed extensively elsewhere , 4, 35: Traditional cardiovascular risk factors, including hypertension, hypercholesterolemia, smoking, and diabetes, probably contribute to coronary microvascular dysfunction, particularly through impairment of endothelium-dependent vasodilatation . Other aThe non-ischemic hypothesis describes altered pain perception as an etiology of CSX. Previous research has demonstrated that patients with chest pain and normal coronary arteries have increased pain sensitivity to peripheral stimuli including electrical and thermal skin stimulation , 45. RecAlthough CSX is often a diagnosis of exclusion, having a high clinical suspicion will help in the recognition of this syndrome. First, non-cardiac etiologies of chest pain, including musculoskeletal, psychiatric, gastrointestinal, and pulmonary disorders, must be excluded. Those with angina-like chest pain, and even some with atypical features, including more frequent or persistent pain  and incoAfter demonstrating evidence of myocardial ischemia, patients should undergo cardiac catheterization or other direct imaging of the coronary arteries to confirm the presence or absence of significant epicardial atherosclerotic stenosis. The use of controlled vasoconstrictor stimulation with ergonovine or acetylcholine has been proposed to rule out coronary artery spasm as a cause of chest discomfort . However1).Managing patients with CSX can be frustrating for both patients and physicians, as there is a lack of data regarding an optimal treatment algorithm. Most studies are observational or only involve a small sample size, yielding conflicting results. The myriad of therapy options are not always efficacious for an individual patient and often require frequent re-assessment and individual tailoring. The main goals of treatment are to improve symptoms, mainly by using anti-anginal therapies, but also through pain modulation. Given the overall favorable prognosis for hard cardiovascular outcomes, it is unclear whether agents such as aspirin, statins, anti-hypertensive medications, etc. that modify cardiovascular outcomes have an additional role in this entity. Below is a detailed discussion of the therapeutic modalities now being utilized. Unless otherwise specified, the data presented involve both genders and subjects with a strict definition of CSX   provide conflicting results. In a cross-over trial of 25 post-menopausal women with CSX receiving a 17β-estradiol patch and placebo for eight weeks each, chest pain episodes decreased in frequency while receiving hormonal therapy . HoweverGiven the reported role of the renin-angiotensin system in promoting microvascular dysfunction, angiotensin-converting enzyme (ACE) inhibitors have been proposed as potential therapies for CSX. In a small placebo-controlled trial, enalapril improved exercise treadmill performance in such patients . More reOutside of their lipid lowering properties, statins have been shown to decrease inflammation and improve endothelial function , 33. As The combination of an ACE inhibitor and a statin may amplify the salutary effects on microvascular function by inhibiting oxidative stress, thereby improving endothelial function. One study randomized 45 subjects with CSX to the combination of ramipril and atorvastatin or to placebo for six months. At follow-up, only those that received ramipril and atorvastatin had increased FMD, as well as improved quality of life and exercise duration .et al., 60 subjects were randomized to clonidine, imipramine, or placebo for three weeks [Another way to improve symptoms experienced by patients with CSX is through pain modulation. Imipramine, typically used in chronic pain syndromes, blocks norepinephrine reuptake and enhances the inhibitory action of pain-modulating neurons. In a placebo-controlled, double-blinded study done by Cannon ee weeks . Imipramee weeks . Spinal ee weeks , 73.A related procedure called transdermal electric nerve stimulation (TENS) has also demonstrated encouraging results. Studies showed that TENS increases coronary blood flow without changing the epicardial vessel diameter, thus exerting its effect on the microvasculature , 75. In et al. provided 13 hypertensive patients with CSX oral L-arginine, which improved angina, resting systolic blood pressure, and quality of life [More recently, there has been interest in modulators of the vasodilator nitric oxide (NO) as contributors to endothelial dysfunction in CSX. ADMA, an inhibitor of NO synthase, is elevated in patients with CSX. In contrast, L-arginine, a precursor of NO, augments vascular dilation and the ratio of L-arginine to ADMA provides an index of systemic NO metabolism. In a study of 9 patients with CSX and 14 control subjects, the continuous infusion of L-arginine increased basal forearm blood flow and reversed the effects of ADMA . In addi of life .As many patients with CSX are insulin resistant , leadingOther pharmacological therapies that have been considered but failed to demonstrate a benefit in CSX include α-antagonists (doxazosin or clonidine)  and the et al. demonstrated that nicorandil injection significantly improved anginal symptoms and ST segment depressions in those with small vessel disease by augmenting coronary blood flow [et al., oral nicorandil moderately ameliorated exercise-induced angina in those with microvascular ischemia [Nicorandil, an activator of vascular potassium channels that has coronary vasodilator properties, warrants further study in patients with CSX. Yamabe ood flow . In anotischemia . RanolazBasal superoxide production by circulating mononuclear cells contributes to intravascular oxidative stress and predicts future cardiovascular events in patients with CSX . AllopurAnother therapy used for refractory angina that holds promise for CSX is extracorporeal enhanced counter pulsation (EECP). This treatment involves the sequential inflation and deflation of a series of cuffs on the lower extremities which is thought to improve endothelial function, amongst other beneficial effects, by mimicking an exercise training effect of shear forces on the vasculature. In fact, a recent small case series demonstrated a sustained improvement in anginal symptoms with EECP in this population .et al. [et al. explored cardiac rehabilitation as a treatment for CSX and found improved exercise tolerance, quality of life, chest pain symptoms, and psychological morbidity with an 8-week phase III cardiac rehabilitation program [Lifestyle modification is an integral component of therapy for patients with CSX, despite limited studies to date evaluating its role. At minimum, lifestyle therapies will favorably impact the adverse cardiovascular risk factor profile in many patients with CSX, but may also have additional beneficial effects specific to this disease. Exercise training improves angina, exercise capacity, and mortality in patients with coronary disease and can similarly improve symptoms in patients with CSX, as shown in a small study by Eriksson et al. . The incet al. . Additio program .Given the association of obesity  and smokAwareness of CSX is imperative, as it is quite prevalent, accounting for up to 60% of the female population undergoing cardiac catheterization for angina. Once non-cardiac sources of chest pain are ruled-out and a positive stress test is found, the patient should undergo either non-invasive imaging (computed tomography or magnetic resonance imaging) or invasive imaging (cardiac catheterization) of his/her coronaries. If normal coronary arteries or non-obstructive disease are identified, the presumptive diagnosis of CSX can be made, although additional assessment of coronary microvascular function when feasible may provide a more definitive diagnosis and have prognostic implications. The initial management begins with lifestyle modification, as well as CAD risk factor reduction, including the empiric use of statins and ACE inhibitors in those with borderline or elevated risk factors. Pharmacotherapy focused on improving symptoms starts with beta-blockade, and the addition of nitrates and calcium channel blockers should be considered for second line therapy. Additional agents that can be considered include estrogen replacement therapy in postmenopausal women and metformin in those with impaired fasting glucose or impaired glucose tolerance. Refractory cases may benefit from referral to a structured cardiac rehabilitation program for supervised exercise training, or to a center with EECP capabilities. Imipramine may also be considered in such cases, as well as neurostimulation via TENS or implantation of spinal cord stimulators for those with persistent debilitating symptoms.It has become quite clear that CSX is not a benign illness in terms of long term morbidity and large, randomized controlled trials to elucidate effective therapies for these patients are sorely lacking. Practitioners and researchers should adhere to and utilize a uniform definition of CSX in their clinical practice and studies, and clearly delineate when they are evaluating CSX versus the broader entity of chest pain with normal angiograms. Further studies are needed to better define risk factors associated with CSX to aid in the identification of affected individuals and to treat the root causes of the disease. Also, these characteristics may aid in the decision as to whether certain patients can undergo non-invasive angiography with CT scanning for evaluation of angina and positive stress tests given the large proportion of normal invasive tests in these women.


Depression has been associated with impaired neurotransmission of serotonergic, norepinephrinergic, and dopaminergic pathways, although most pharmacologic treatment strategies for depression enhance only serotonin and norepinephrine neurotransmission. Current drug development efforts are aimed at a new class of antidepressants which inhibit the reuptake of all three neurotransmitters in the hope of creating medications with broader efficacy and/or quicker onset of action. The current review explores limitations of presently available antidepressants and the history and premise behind the movement to devise triple reuptake inhibitors. The evidence for and against the claim that broader spectrum agents are more efficacious is discussed. Examples of triple reuptake inhibitors in development are compared, and preclinical and clinical research with these agents to date is described. Since the catecholamine hypothesis of depression was first described in the 1960’s, most antidepressant drug development has targeted the enhancement of monoamine neurotransmission. For decades tricyclic antidepressants (TCAs), which inhibit the reuptake of norepinephrine and serotonin, were the principal treatment choice for clinicians; unfortunately these agents have classic side effects as a result of histaminergic, cholinergic, and alpha-adrenergic receptor antagonism. Additionally, TCAs have a low therapeutic index related to quinidine-like cardiac conduction effects which make them quite dangerous in overdose. Monoamine oxidase inhibitors have also been in use for approximately fifty years, but their inhibition of monoamine catabolism predisposes them to drug-drug interactions as well as interactions with dietary tyramine. In the past two decades, antidepressant drug development efforts have focused on improving tolerability which has led to molecules that specifically inhibit serotonin reuptake (SSRI) or both serotonin and norepinephrine reuptake (SNRI). These agents have more benign side effect profiles than TCAs or monoamine oxidase inhibitors (MAOIs), although they have not shown advantages in efficacy or in onset of antidepressant response ,48. To dvia other mechanisms; such medications include mirtazepine , as well as trazodone and nefazodone (primarily presynaptic and postsynaptic 5-HT2 antagonists). Less attention has been given to affecting dopamine transmission in depression, although data indicate the important role of mesolimbic dopamine in moderating motivation and reward-related behavior which are typically disrupted in depression [Copious evidence links depression to deficiencies in neurotransmission of the monoamines serotonin, norepinephrine, and dopamine ,35,43,54pression ,44. Furtpression , and it pression ,56. Addipression ,18,52, Mpression ,14, and pression , 49. FinPrior to the 1980’s, drug candidates were identified by testing laboratory-derived compounds in animal models and observing the effects. As biochemical and genetic research identified the molecular mechanisms that underlie disease, drug development began to focus on increasing selectivity with the goal of affecting only the target molecule identified as relevant in order to minimize side effects . HoweverIn a reversal of the move towards selectivity that led to the SSRIs in the 1980’s and 1990’s, the SNRIs were developed under the premise that a broader spectrum of neurotransmitter reuptake inhibition would lead to greater antidepressant efficacy and/or more rapid onset of action. Data accumulated to date is mixed regarding the usefulness of this strategy. With regard to rapidity of onset, venlafaxine performed well in a placebo-controlled trial in hospitalized depressed patients, demonstrating efficacy benefit within one week of treatment initiation . SimilarOther data endorse the thrust towards increased neurotransmitter selectivity. In particular, a meta-analysis of the highly selective SSRI escitalopram  suggests that this medication is superior in efficacy to other SSRIs and to the SNRI venlafaxine (grouped together) on the outcomes of response rate, remission rate, and overall treatment outcome . A seconin vitro differences in selectivity are poorly understood.It should also be noted that currently available dual reuptake inhibitors differ in their relative potencies at monoamine transporters. Milnacipran blocks serotonin and norepinephrine reuptake equally, whereas greater selectivity at serotonin reuptake sites is characteristic of venlafaxine (30-fold) and duloxetine (10-fold) . Clinicain vitro [Despite the structural similarity of the norepinephrine, serotonin, and dopamine transporters, synthesis of bioavailable and safe molecules which appreciably inhibit all three transporters has been challenging . Additioin vitro . To date1) [in vitro with a relative potency of NE:SER:DA of 1:2:17 [DOV Pharmaceutical, Inc. has developed triple reuptake inhibitors from a class of azabicyclohexanes chemically related to bicifadine. Three of these compounds  have been shown to block transport of human recombinant NE, SER, and DA transporters with clinically-relevant potency (Table 1) ,44, 45. 1) , and 216The novel triple reuptake inhibitor tesofensine (NS 2330) has not been systematically studied regarding its clinical or preclinical antidepressant effects. Similar to antidepressants , this ag1.It is likely that other triple reuptake inhibitors are in various developmental phases, and the current discussion of compounds in development should not be considered exhaustive. A summary of described compounds appears below in Table Like other classes of antidepressant medications, triple reuptake inhibitors likely hold promise for a variety of therapeutic indications. One emerging area of research concerns the potential antinociceptive effects of triple inhibitors, which is expected given the copious data supporting the utility of TCAs and SNRIs for pain syndromes. Preclinical research with bicifadine demonstrates its antinociceptive effects in animal models of acute, persistent, and chronic pain including inflammatory, visceral, and nociceptive paradigms. These effects were reduced in some experimental conditions by the coadminstration of sulpride (a dopamine-2 receptor antagonist), suggesting that enhancement of dopamine neurotransmission is important for the full antinociceptive effect of bicifadine .The prodopaminergic potential of tesofensine led to a proof-of-concept study of this agent in the treatment of Parkinson’s disease (PD). In this adequately-powered study (N=261) with multiple dosage arms corresponding to up to 77% DA transporter occupancy, tesofensine did not outperform placebo . Two smaWeight loss has been observed as an adverse event in studies of tesofensine , promptiOne published preclinical study describes the effect of the “balanced” triple reuptake inhibitor DOV 102,677 in reducing volitional alcohol consumption in ethanol-preferring rats without decreasing food or water consumption . It shouThe impetus to develop triple reuptake inhibitors is a natural consequence of the rich drug development history occurring over the past fifty years. We have come a long way since the serendipitous discovery that TCAs and MAOIs exert antidepressant effects. Rational drug design has allowed us to customize the receptor profiles of potential antidepressant drugs and to target specific monoamine reuptake transporters. Current strategies involve developing multiple analogues of dual reuptake inhibitors and characterizing their receptor profiles in order to develop a quiver of molecules with clinically-relevant activity at all three monoamine reuptake sites. The ideal ratio of transporter site potencies that a triple reuptake inhibitor should exhibit remains unknown, and hopefully the diversity of molecules in development will shed light on this issue. Future research will undoubtedly involve clinical study of various triple reuptake inhibitors to determine whether any of them offer advantages over currently approved antidepressants in efficacy, rapidity of onset, or side effect profile. Research published to date tends to support that antidepressants vary modestly in various outcomes related to efficacy. Yet, findings are mixed regarding whether broader spectrum agents or highly serotonin-selective agents confer the best efficacy. Furthermore, concern has been expressed that triple reuptake inhibitors may produce broader side effect burden without enhancing efficacy over more selective agents . In actu


Atherosclerosis is a chronic, progressive, inflammatory disease with a long asymptomatic phase. Disease progression can lead eventually to the occurrence of acute cardiovascular events such as myocardial infarction, unstable angina pectoris and sudden cardiac death. While the disease is still in a subclinical stage, however, the presence of atherosclerosis can be identified by several methods, including coronary angiography, intravascular ultrasonography, B-mode ultrasonography, computed tomography and magnetic resonance imaging. Based on the results of imaging studies, statin therapy can slow, halt or even reverse the progression of atherosclerotic disease, depending on the intensity of treatment. Whether to screen and treat patients for subclinical atherosclerosis remains controversial. Although atheromatous plaque burden reduction has not yet been definitively correlated with significant decreases in risk for acute coronary events in asymptomatic patients, statin therapy contributes significantly to the risk reduction observed in clinical trials in patients with and without overt coronary disease. Atherosclerotic disease in both its subclinical and clinically established phases is widely prevalent throughout the world. A variety of imaging modalities  have been developed to detect and better define the burden of atherosclerotic lesions in individuals at risk for cardiovascular disease. Statin therapy has been shown to reduce cardiovascular morbidity and mortality in a wide spectrum of patient populations. It is becoming increasingly apparent that statins also impact the course of atherogenesis. The major controlled, randomized studies evaluating the capacity of statin therapy to positively impact the progression of atherosclerotic disease are reviewed herein.Arterial imaging of both the carotid and coronary vasculature can be used to further refine risk based on Framingham risk scoring. Statin therapy favorably impacts rates of atherogenesis. High-dose statin therapy and aggressive low-density lipoprotein cholesterol lowering are associated with atheromatous plaque stabilization and even regression. If subclinical atherosclerotic disease is detected, strong consideration should be given to coupling lifestyle modification with statin therapy, irrespective of overall risk factor burden.In 2004, coronary heart disease (CHD) affected an estimated 15.8 million people in the USA and was responsible for one of every five deaths, making it the single largest cause of mortality in American men and women  men killed during the Vietnam conflict demonstrated that almost 50% had some evidence of coronary atherosclerosis . SimilarAtherogenesis begins at sites of endothelial injury. Such injury may result from a variety of factors, including increased local shear forces from hypertension, elevated plasma concentrations of LDL-C and remnant lipoprotein particles, chemical toxins in cigarette smoke, low serum HDL-C and impaired reverse cholesterol transport, insulin resistance, and glycosylated end product formation in diabetes mellitus, among others  7–9). T–9. T7–9)T-lymphocytes and other mediators of inflammation and immunity infiltrate the developing lesion site from both the intimal and adventitial aspects of the vessel wall . Once loThe cytokines released as part of the inflammatory cascade stimulate production of interleukin-6, which in turn stimulates the production of C-reactive protein (CRP) and other acute-phase reactants . It is iThe stability of the advanced atherosclerotic lesion or plaque depends on its cellular and extracellular contents. Plaques with small lipid cores, thick fibrous caps, few inflammatory cells and a preponderance of smooth muscle cells are typically stable; conversely, those with large lipid cores, thin fibrous caps, numerous macrophages and relatively few smooth muscle cells are most likely to rupture ,14. ActiPlaque rupture usually occurs at the base of the fibrous cap, which is usually thin and contains relatively few smooth muscle cells and many inflammatory cells. When the plaque ruptures, platelets and coagulation factors in circulating blood are exposed to the thrombogenic contents of the plaque’s extracellular matrix and lipid core, including collagen, phospholipids and tissue factor ,13. TherMany plaque ruptures are clinically silent but can be detected on postmortem assessment as breaks in the fibrous cap associated with evidence of healing . In a coThe prevalence and extent of atherosclerosis increase with age. In the Framingham risk assessment, age is used as a surrogate for coronary plaque burden, but plaque burden is the true risk factor for CHD-related morbidity and mortality . BecauseMarkers of inflammation are regarded as surrogates of asymptomatic atherosclerosis, inasmuch as inflammation plays a central role in the atherogenic process. Higher CRP levels have been consistently associated with increased risk for major cardiovascular events across numerous populations and have also been shown to add prognostic information to LDL-C levels and Framingham risk scores . HoweverAlthough the exact prevalence of subclinical atherosclerosis is undetermined, it is noteworthy that 50% of men and 64% of women in the USA who die suddenly from CHD have no prior manifestation of disease, and the majority of these individuals were not considered to be at high risk according to Framingham risk stratification. In an assessment of more than 5000 adults aged ≥ 65 years participating in the Cardiovascular Health Study, the prevalence of subclinical atherosclerotic disease was 36% in women and 38.7% in men and increased with age . In a laA plethora of studies have found increased prevalence of subclinical atherosclerosis as measured by CT and/or carotid ultrasound in discrete population groups without evidence of CHD, including postmenopausal women , women wA variety of invasive and non-invasive techniques are available to measure atherosclerosis and subclinical atherosclerosis . These tB-mode ultrasonography can determine the combined thickness of the arterial intimal and medial layers, usually measured in the common carotid artery . The carElectron-beam CT, which is used clinically, measures coronary artery calcification. Coronary calcium reflects plaque burden, because calcium deposits are related to the lipid and apoptotic remnants of the plaque . CoronarContrast-enhanced multislice CT, also known as MDCT, uses electrocardiogram-gated images to quantify atherosclerotic calcification in the coronary arteries ,44. BecaCoronary angiography localises plaque and reveals degrees of coronary luminal stenosis . Although the presence and number of high-grade stenoses are associated with increased risk of future coronary events, angiography cannot identify culprit lesions that are prone to rupture and cause acute coronary syndromes (ACS) . IntravaThe promise of these techniques is that a single measurement can provide valuable information about the distribution and localisation of subclinical atherosclerosis. Serial measurements made over time provide the opportunity to evaluate the impact of risk factor treatment on atherosclerotic disease progression and, perhaps, changes in risk for ACS.To determine whether carotid IMT improved prediction of coronary events compared with the Framingham Risk Score, Baldassarre et al.  studied Two recently published meta-analyses were conducted to determine the extent to which surrogate markers for atherosclerosis predict future cardiovascular end-points. Simon et al.  used pubLorenz et al.  performeAtherosclerosis is a chronic and progressive disease whose optimal prevention requires lifelong attention to diet and exercise, smoking abstinence, and aggressive risk factor identification and treatment. National and international treatment guidelines recognise the importance of LDL-C in driving atherogenesis and CHD risk and recommend stratified target LDL-C levels for reducing this risk. When diet and exercise alone are not sufficient for achieving the LDL-C goal, statin therapy is most frequently initiated. Numerous studies have shown that statins not only reduce CHD morbidity and mortality but also decrease the rate of atherosclerotic disease progression and, under some circumstances, can even induce the regression of atherosclerotic plaque ,49–53.In studies using B-mode ultrasonography in patients with CHD, statin therapy slows the rate of atherosclerosis progression in the carotid artery. In an early study, pravastatin 40 mg/day reduced progression of atherosclerosis by 35% in the common carotid artery over a 3-year period; the carotid IMT increased by a mean of 0.029 mm/year with pravastatin compared with 0.046 mm/year with placebo (p = 0.03) . HoweverStudies using IVUS imaging have yielded more dramatic results, and the clinical benefits were related, once again, to the intensity of statin therapy. The Reversal of Atherosclerosis with Aggressive Lipid Lowering trial  comparedAggressive statin therapy reduces carotid IMT in patients with familial hypercholesterolaemia, a population at high risk of premature CHD. In the 2-year Atorvastatin versus Simvastatin on Atherosclerosis Progression trial , a randoAggressive statin therapy with rosuvastatin was recently shown to arrest atherosclerotic disease progression. The Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin (METEOR) study  enrolledThe effect of conservative vs. aggressive statin treatment on carotid atherosclerosis was also evaluated by high-resolution MRI . A totalSeveral studies have compared the effects of intensive vs. conventional statin therapy on coronary artery calcification measured by EBCT in subjects with subclinical atherosclerosis ,59. OverAs the technology for early diagnosis of atherosclerosis advances and becomes available for clinical use, a key question is who should be screened. In 2006, the American Heart Association Committee on Cardiovascular Imaging and Intervention issued a scientific statement on the clinical utility of detecting calcified plaque and the appropriate use of CT in a variety of clinical situations . A cliniIn several early studies, reductions in surrogate outcomes with lipid-lowering treatment appeared to correlate highly with reductions in cardiovascular events ,62,63. HThe clinical significance of reducing the volume of atherosclerotic lesions using lipid-lowering treatment has not been established, and studies using surrogate end-points have not yet evaluated the magnitude of effects on clinical end-points. For example, we do not yet know how much plaque reduction would be required to lower cardiovascular risk by 10%, 20% or more. We do know that in a diffuse condition such as atherosclerosis, aggressive and comprehensive risk factor management provides equal efficacy in reducing risk for ACS compared with prophylactic percutaneous transluminal angioplasty with stenting . TherefoAtherosclerosis is a chronic and progressive disease that causes substantial cardiovascular morbidity and mortality. Although often detected when patients first experience a major cardiovascular event, several techniques can be used to identify atherosclerosis when it is still in its subclinical stages. Reducing atherogenic lipoprotein burden with statin therapy is associated with significant changes in rates of coronary and carotid atherosclerosis disease progression. Some degree of plaque regression can be observed with aggressive statin therapy to lower LDL-C. As shown in the Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis in Myocardial Infarction 22 trial , such ag


Neurological dysfunction is an important manifestation of inherited metabolic disorders. Although these are more common in childhood, adult onset forms with a different clinical presentation are often encountered. Recent advances in the diagnosis and treatment of these conditions have substantially improved the outcome in many of these conditions. This makes it essential that the practicing physician be familiar with the clinical presentation and diagnosis of these disorders. For the evaluation of a patient with a possible inborn error of metabolism, simple screening tests may aid in the diagnosis and provide direction for more comprehensive laboratory analysis. In this review, we present a practical approach to diagnosis of neurometabolic disorders. Establishing a specific diagnosis in these disorders will enable the clinician in offering a definitive long-term treatment, prognosis and genetic counselling. Metabolic disorders caused by genetic mutations resulting in enzyme deficiencies in an intermediary metabolic pathway constitute a wide spectrum of diseases in clinical practice. The term ‘inborn errors of metabolism’ was introduced by Sir Archibald Garrod at the beginning of the twentieth century. Since thOver one-third of the inherited metabolic disorders are characterized by the central nervous system involvement and neurological symptoms are the presenting and the most prominent clinical problems associated with them. Among the neurometabolic disorders, there are particularly five common neurological presentations: chronic encephalopathy, acute encephalopathy, movement disorder, myopathy and psychiatric or behavioral abnormalities.Of all neurological problems that occur in patients with inherited neurometabolic disorders, developmental delay or psychomotor retardation is the most common. The cognitive disabilities caused by these disorders tend to be at a global level, affecting all spheres of development to some extent. They are usually progressive and associated with other objective evidences of neurological dysfunction such as disorders of muscle tone, impairment of special senses, seizures, pyramidal tract signs, evidences of extrapyramidal deficits or cranial nerve deficits. Routine screening for inborn errors of metabolism in children with developmental delay has a diagnostic yield of approximately 1% that can increase to 5% in specific situations such as in the case of relatively homogenous and isolated populations or if there are clinical indicators. A generaAcute encephalopathy presents in a number of neurometabolic disorders, particularly in children. Major in2 gangliosidosis and Niemann-Pick type C), abetalipoproteinemia, mitochondrial electron transport chain defects, neuronal ceroid lipofuscinosis, Refsum disease and Hartnup disease. The The29] TThe normal physiological response to decreased glucose production is increased mitochondrial fatty acid β-oxidation and the production of ketones. Accordingly, increased urinary ketones provide an indirect evidence of whether hypoglycemia is the result of inadequate production or overutilization of glucose. In older infants, children and adults, the absence of ketones in urine is usually a strong indication of increased glucose utilization. Increased glucose utilization (hypoketotic hypoglycemia) occurs as a result of either hyperinsulinism or of primary or secondary defect in fatty acid oxidation. The two situations are distinguishable by measuring plasma free fatty acid levels. One of the physiological effects of insulin is inhibition of hormone-sensitive lipase in adipose tissue. Low free fatty acid levels during hypoglycemia are a strong indication of abnormally elevated insulin levels. The timing of the hypoglycemia and other laboratory findings render differentiation of this condition relatively simple. Hyperinsulinemic hypoglycemia occurs due to insulin hypersecretion by the islets of Langerhans. Focal islet cell hyperplasia is associated with mutation of sulfonylurea receptor (SUR1) or inwardly rectifying potassium channel (Kir.2) genes. A few cases of syndromic hyperinsulinemia such as hyperinsulinism associated with Usher syndrome type Ic, congenital disorder of glycosylation (CDG) Ia or Ib, Beckwith Wiedemann's syndrome, Perlman's or Sotos' syndrome have been described. Infants with mutations in glutamate dehydrogenase gene (GLUD I) present with recurrent hypoketotic hypoglycemia, elevated plasma insulin and persistent hyperammonemia.Most hypoglycemias associated with permanent hepatomegaly occur due to an inherited metabolic disorder. All condHypoglycemia is a prominent secondary metabolic phenomenon in all mitochondrial fatty acid β-oxidation defects. The diagnosis can be confirmed by demonstrating the presence of high concentration of C6–C10 dicarboxylic acids  and the characteristic acylcarnitines in plasma during acute decompensation. Fasting hypoglycemia and marked hepatomegaly associated with early-onset renal tubular dysfunction characterised by polyuria, hypophosphatemic rickets, hyperchloremic metabolic acidosis, and severe growth retardation is typical of Fanconi-Bickel syndrome. This condition is caused by mutation in GLUT 2 gene coding for the hepatic-type glucose transporter.Patients with genetic endocrine disorders due to defects such as growth hormone (GH) gene deletion, mutation in GH-releasing hormone (GHRH) receptors, insulin-like growth factor-1 (IGF-1) defects or malformations of the hypothalamic area leading to multiple pituitary hormone deficiencies can present with fasting hypoglycemia. Hypoglycemic responsiveness to glucagon is variable—mild, absent or dramatic—the latter response being similar to that observed in hyperinsulinism. Hypoglycemia associated with isolated adrenocorticotrophic hormone (ACTH) deficiency is rare. Glucagon deficiency can also be associated with hypoglycemia.The second most important laboratory feature of many inherited neurometabolic disorders during episodes of illness is metabolic acidosis that is demonstrated by measuring arterial blood gases and bicarbonate. An increased anion gap (>16) is observed in many of these disorders due to the accumulation of fixed acids such lactic acid, ketoacids and other organic acids . DiagnosMetabolic acidosis with a normal anion gap is noted in renal tubular acidosis or diarrhea. A history of diarrhea is usually sufficient to distinguish hyperchloremic metabolic acidosis due to excessive gastrointestinal bicarbonate losses from that arising from renal tubular dysfunction. Metabolic disorders associated with renal tubular acidosis include hereditary fructose intolerance, hepatorenal tyrosinemia, cystinosis, Fanconi-Bickel syndrome, Lowe syndrome, vitamin D dependency and congenital lactic acidosis due to cytochrome c oxidase deficiency.Defects of pyruvate metabolismPyruvate dehydrogenase deficiencyPyruvate carboxylase deficiencyDefects of NADH oxidationMitochondrial electron transfer chain defectsDisorders of gluconeogenesis/glycogen storage disordersGlucose 6-phosphatase deficiency (GSD I)Fructose 1,6- bisphosphatase deficiencyPhosphoenolpyruvate carboxykinase deficiencyGlycogen debrancher deficiency (GSD III)Glycogen synthase deficiency (GSD 0)Fatty acid oxidation defectsDefects of biotin metabolismBiotinidase deficiencyHolocarboxylase synthase deficiencyDefects of organic acid metabolismPropionic acidemiaMethylmalonic acidemiaOthersHereditary fructose intoleranceLactate and pyruvate are normal metabolites. Their plasma levels depend upon the equilibrium between their cytoplasmic production from glycolysis and their consumption by different tissues. Abnormal accumulation of lactic acid is a common cause of pathological metabolic acidosis. In a majority of cases, it is caused by tissue hypoxia resulting from inadequate oxygen supply or poor circulation. Blood lactate accumulates in circulatory collapse, hypoxic insult and other conditions involving failure of cellular respiration. These conditions should be ruled out before investigating for an inborn error of lactate pyruvate. Ketosis is absent in most hyperlactacidemias secondary to tissue hypoxia, while it is a nearly constant finding in most inherited metabolic disorders except pyruvate dehydrogenase deficiency, glycogen storage disorder type I and fatty acid oxidation defects. Following are the inherited metabolic causes of lactic acidosis:The differential diagnosis of elevated lactate in neurometabolic disorders is shown in Ketonuria is a physiological finding in many cases of late infancy, childhood and even adolescence. Ketosis, which is not associated with acidosis, hyperlactacidemia or hypoglycemia, is likely to be a normal physiological indication of the nutritional state . It may be the cause or consequence of repeated vomiting in infants and children. However, hyperketosis at a level that produces metabolic acidosis is not physiological. Hyperglycemia associated with ketosis indicates the presence of diabetes mellitus.Ketolytic defects (succinyl-CoA: oxo-acid transferase and 3-ketothiolase deficiencies) can present as moderate ketonuria occurring mainly in the fed state at the end of the day. Severe fUrea cycle defectsN-Acetylglutamate synthetase (NAGS) deficiencyCarbamoyl phosphate synthetase I (CPS I) deficiencyOrnithine transcarbamoylase (OTC) deficiencyArgininosuccinate synthetase (AS) deficiencyArgininosuccinate lyase (AL) deficiencyArginase deficiencyOrganic acidemiasIsovaleric acidemiaPropionic acidemiaMethylmalonic acidemiaGlutaric aciduria type IIMultiple carboxylase deficiency3-Ketothiolase deficiencyCongenital lactic acidosisPyruvate dehydrogenase deficiencyPyruvate carboxylase deficiencyMitochondrial respiratory chain defectsFatty acid oxidation defectsMedium-chain acyl-CoA dehydrogenase (MCAD) deficiencyLong-chain acyl-CoA dehydrogenase (LCAD) deficiencySystemic carnitine deficiencyDibasic amino acid transport defectsLysinuric protein intoleranceHyperornithinemia Hyperammonemia Homocitrullinuria (HHH) syndromeHyperammonemia secondary to hepatic dysfunctionTyrosinemia type I1-Antitrypsin deficiencyαGalactosemiaBile acid synthesis defectsRespiratory chain defectsOthersGlutamate dehydrogenase deficiency (hyperinsulinemia-hyperammonemia syndrome)Hyperammonemia is an important laboratory finding associated with neurometabolic disorders presenting mainly with acute encephalopathy. Normally, plasma ammonium is less than 50 µmol/l (reference range: 15–35 µmol/l); however, it may slightly increase as a result of high protein intake, exercise, or a hemolysed sample. Plasma ammonium levels are also often elevated in patients with severe hepatocellular dysfunction irrespective of the cause, including viral infection, intoxications and infection with urease-positive bacteria, particularly with stasis in the urinary tract, Reye syndrome, valproate therapy and leukemia therapy, including treatment with asparaginase. Following are the inherited metabolic disorders presenting with hyperammonemia:A widely used algorithmic approach to the differential diagnosis of hyperammonemic encephalopathy is presented in Analysis of amino acids in various physiological fluids such as plasma, urine and cerebrospinal fluid is central to the investigation of a possible neurometabolic disorder. Some laboratories include a selection of relatively nonspecific chemical tests for the presence of compounds containing certain functional groups such as disulfides by using the cyanide nitroprusside test, etc. However, the presence of large amounts of interfering compounds sometimes makes these methods unreliable. Paper or thin layer chromatography of amino acids in plasma and urine and visualisation by treatment with ninhydrin is useful for detecting excess amino acids such as phenylalanine in phenylketonuria. Quantitative amino acid analysis by ion-exchange chromatography, high-pressure liquid chromatography (HPLC) or tandem mass spectrometry (MS-MS) provides confirmation of the identity and concentrations of the amino acids and provides accurate information on the levels of amino acids that may be present in subnormal concentrations. These methods are also necessary to quantitate reliably the concentration of amino acids in fluids such as CSF.In inborn errors of specific amino acid metabolism, marked increases are observed in plasma and urine, which are sufficiently specific to suggest a diagnosis. Secondary abnormalities of amino acid concentrations in plasma and urine are also very common. Severe hepatocellular disease, renal tubular disease, catabolic states, malnutrition, malignancy, infections, pregnancy, vitamin deficiencies, burns and other injuries are all associated with the disturbances of amino acid concentrations in plasma, urine or both. Increased amino acid levels in the urine in the absence of corresponding increases in plasma levels occur generally due to inherited or acquired renal transport defects. An important point to be considered is that the concentrations of various amino acids in plasma depend on the metabolic state of the individual. During the postprandial period, the levels of essential amino acids, phenylalanine, tyrosine, lysine, valine, leucine, isoleucine, etc, are increased. Prolonged fasting will result in an elevation of the branched-chain amino acids, leucine, isoleucine and valine. The reference values are based on plasma collected 4–6 h after the last meal.Organic acids comprise key metabolites of virtually all pathways of intermediary metabolism as well as exogenous compounds. They are generally determined in urine by the gas chromatography-mass spectrometry (GC-MS), although diagnostically important organic acid changes occur in a variety of physiological fluids. Preparation of the analysis includes preliminary extraction of the organic acids from urine into an organic solvent; this is followed by derivatization to form trimethysilyl derivatives to lower the temperature at which they vaporise and to prevent them from undergoing thermal decomposition, before injecting into the GC-MS. The preliminary identification of the organic acids is based on the retention time, that is, the time taken by the compound to pass through the column. The interpretation of organic acid analysis depends on several key diagnostic metabolites as well as the characteristic patterns of abnormalities.1 gangliosidosis and multiple sulfatase deficiency.Urinary excretion of mucopolysaccharides is typically increased in the case of mucopolysaccharidoses, GMExcess acidic mucopolysaccharides in urine can be detected and quantified by measuring the change in color of metachromatic dyes such as Alcian blue, dimethylmethylene blue or toluidine blue. Although qualitative spot tests, such as the Berry spot test, are rapid and inexpensive, they produce many false-positive and false-negative results. Uni- or bidirectional electrophoresis or thin layer chromatography of urinary mucopolysaccharides provides information that is important for the classification of the disorders by indicating the relative proportions of specific mucopolysaccharides.The oligosaccharides in urine are produced by the incomplete breakdown of the carbohydrate side chains of complex glycoproteins. Analysis of urine oligosaccharides is an inexpensive, although not very specific, screening test for glycoproteinoses. The most widely used method is thin layer chromatography of diluted urine. Increased amounts of free sialic acid are excreted in the case of sialic acid storage disorders and can be determined in urine by spectrophotometry.Analysis of carnitine and glycine esters has become an important part of the investigation of organic acidopathies and disorders of mitochondrial β-oxidation. One of the most important advances in the application of diagnostic laboratory technology has been the introduction of MS-MS for the assay of carnitine profile, which allows the detection of many defects of mitochondrial β-oxidation. Compounds eluted from dried blood spots can be used for analyzing acylcarnitines.Measuring plasma total carnitine is also helpful in determining the presence of a fatty acid oxidation disorder. All but one is associated with either an increased or decreased concentration of total carnitine in the plasma and tissues. In carnitine transporter defect, plasma carnitine levels are severely decreased . In carnitine palmitoyl transferase-1 (CPT-I) deficiency, total carnitine levels are increased . In all other defects of fatty acid β-oxidation, total carnitine levels are reduced to 25–50%.The quantitative analysis of the very-long-chain fatty acids (VLCFA) is required for the differential diagnosis of various peroxisomal disorders. The characteristic biochemical abnormalities in some of these disorders are summarized in Plasmalogens are the major components of the phospholipids of myelin and other membranes, including the red blood corpuscles. In peroxisomal biogenesis disorders, a deficiency of plasmalogen biosynthesis occurs, which results in decreased concentrations in myelin and other membranes, including red cell membranes. Plasmalogens are determined by extracting membrane lipids and determining lipid phosphorus after saponification to remove phosphoglycerides.Elevated levels of pipecolic acid, an intermediate in lysine metabolism, in the plasma and urine is characteristic of inherited defects of peroxisomal biogenesis. Pipecolic acid is usually determined by HPLC, gas chromatography or GC-MS. Plasma levels may also be elevated in children with hepatocellular disease or by ingestion of vegetables rich in pipecolate.The final diagnosis of many neurometabolic disorders depends on the ability to demonstrate a specific enzyme deficiency responsible for the disease. Prenatal diagnosis, in particular, requires access to specific enzyme assay in cases in which the diagnosis of the disease under investigation is established. Enzyme analysis can also be used for the detection of carriers. Tandem mass spectrometry (Tandem MS or MS-MS) is a major technological advance in the screening for inherited metabolic diseases. It has t34Molecular genetic studies are increasingly relied on to confirm the diagnosis of many neurometabolic diseases. The advent of molecular genetic testing for carrier detection is a major advance in genetic counselling of family members of individuals affected with lysosomal enzyme diseases in which specific disease-causing mutations have been identified. Nonetheless, there remain some limitations on the general diagnostic use of this methodology. With a few exceptions, in all inherited metabolic diseases for which the gene responsible has been isolated and disease-producing mutations characterized, no single mutation accounts for all cases. Patients may have mutant alleles that have not yet been characterized, or they may be so rare that their routine testing may not be economically feasible. Hence, although the detection of a certain mutation in tissue extracted from a patient is considered a strong support for diagnosis, failure to demonstrate the presence of the mutation does not rule out the diagnosis.MR imaging has emerged as a powerful tool in the study of normal and abnormal brain structure, function and biochemistry. Clinicians can derive significant benefits from specific imaging findings in neurometabolic disorders. Some of In maple syrup urine disease, MRI shows diffuse symmetrical hyperintensities involving the periventricular, deep white matter and subcortical ‘U’ fibers Figure . The othOrganic acidemias are another group of disorders with characteristic neuroimaging findings, which aid in diagnosis. Widening of the sylvian fissure, mesencephalic cistern and expansion of CSF spaces anterior to the temporal lobes are cardinal signs of glutaric aciduria Type-1 . If comb43The characteristic feature of methylmalonic acidemia is severe involvement of the globus pallidus46 Figur. The bilSpecific and effective treatment is possible for many inborn errors due to advances in the understanding of their biochemical basis. Early clinical diagnosis is essential in ensuring that the affected infants will be benefited by these advances. Some of the modalities of treatment include regulation of substrate accumulation by restricted dietary intake , regulation of endogenous production of substrate , acceleration of removal of substrate , replacement of products (thyroxine in inborn errors of thyroid hormone biosynthesis), enzyme replacement and gene transfer therapy. TreatmenEven when treatment options are limited, there are benefits that follow an early diagnosis. A definitive diagnosis in a sick child avoids further unnecessary investigations, permits an accurate assessment of prognosis, and prevents the loss of an opportunity to make the diagnosis in the case of the death of the child. Furthermore, genetic advice can be offered to families with the prospect of prenatal diagnosis for future pregnancies, identification of other affected family members and carrier detection.Diagnosis of neurometabolic disorders always poses difficulty to physicians. This is mainly due to the fact that these disorders are rare and most of them share common clinical manifestations. The main obstacle to making an accurate diagnosis is a failure in considering the possibility clinically. Definitive long-term treatment usually requires that a specific diagnosis is made. With the progress of basic science and technology over the past century, the pathogenesis of these disorders has been understood clearly. This knowledge has opened a possibility of therapeutic intervention for many of these disorders.http://www.mayomedicallaboratories.comhttp://www.aruplab.com


A new era has begun in the treatment of ischemic disease and heart failure. With the discovery that stem cells from diverse organs and tissues, including bone marrow, adipose tissue, umbilical cord blood, and vessel wall, have the potential to improve cardiac function beyond that of conventional pharmacological therapy comes a new field of research aiming at understanding the precise mechanisms of stem cell-mediated cardiac repair. Not only will it be important to determine the most efficacious cell population for cardiac repair, but also whether overlapping, common mechanisms exist. Increasing evidence suggests that one mechanism of action by which cells provide tissue protection and repair may involve paracrine factors, including cytokines and growth factors, released from transplanted stem cells into the surrounding tissue. These paracrine factors have the potential to directly modify the healing process in the heart, including neovascularization, cardiac myocyte apoptosis, inflammation, fibrosis, contractility, bioenergetics, and endogenous repair. Although coronary artery disease accounts for two-thirds of heart failure cases in the United States , other cStem cells are defined as cells that have the capacity to self renew, multipotency/pluriopotency, and clonality, and are divided into embryonic stem cells and adult stem cells. Although embryonic stem cells may have more potential for cardiac differentiation and thus replacement of damaged myocardium, few studies have focused on paracrine factors released from these cells that may be involved in mediating cardiac repair. Therefore, this review will focus on adult stem or adult progenitor cells, since numerous studies suggest that paracrine factors released from these cells may comprise an important mechanism contributing to cardiac protection after their transplantation into the myocardium.Adult stem cells comprise at least three different groups: bone marrow-derived stem cells, the circulating pool of stem or progenitor cells, which, at least in part, are derived from the bone marrow, and tissue-resident stem cells. Bone marrow contains a complex assortment of progenitor cells, including hematopoietic stem cells (HSCs), so-called 'side population cells'  , mesenchAnother population of progenitor cells that has also been shown to have therapeutic potential is the pool of progenitor cells circulating within the blood. Asahara and Isner isolated the so called 'endothelial progenitor cells' (EPCs), defined by their function to form new blood vessels and enhance neovascularization after ischemia  [Review of the literature indicates, regardless of whether 'stem' or 'progenitor' cells consist of a mixture of several cell populations or selected subpopulations, that these cells have the capacity to mediate neovascularization. Kamihata et al.  have shoet al. . Using M [et al.  demonstr [et al. . In the ion (MI) . Overexpion (MI) , suggestAnother population of bone marrow-derived stem cells, MAPCs, was also found to secrete factors such as VEGF, MCP-1, PDGF-BB, and TGF-β, and the authors postulated that this increase in angiogenic factors led to increased vascularity after the intramyocardial injection following MI . Specifiin vivo such that, in ischemic limbs, VEGF is also released from recruited human EPCs. As a functional consequence, conditioned medium of EPCs induced a strong migratory response of mature endothelial cells, which was significantly inhibited by VEGF and SDF-1 neutralizing antibodies. Taken together, EPCs exhibit a high expression of angiogenic growth factors that have a direct effect on mature endothelial cell migration and lead to improved neovascularization after ischemia.Other cell types with angiogenic potential are those isolated and cultured from the circulating pool of mononuclear cells, and these cells express factors that are pro-angiogenic . Specifiin vivo transplanted cells or whether the transplanted cells modulate endogenous tissue cytokine and growth factor levels. In a recent study, Cho et al. [et al. [Altogether, these studies suggest that several types of bone marrow-derived cells, consisting of either a mixture of different types of cells, or selected subpopulations of stem cells and circulating progenitor cells, have the capacity to express and secrete paracrine factors that lead to increased neovascularization following ischemia. Although these studies demonstrate an increased release of paracrine factors into the culture media and increased tissue expression of these paracrine factors upon cell transplantation, only some of the studies address whether these paracrine factors are released from the o et al. , demonst [et al. , using ain vitro and in vivo and led to an upregulation of the well-known anti-apoptotic protein Bcl-2 in cardiac myocytes [in vivo survival of the stem cells themselves has also proven to decrease cardiac myocyte death via the secretion of paracrine factors. The overexpression of the survival protein Akt in MSCs led to a decrease in cardiac myocyte apoptosis in vitro and their myocardial transplantation led to a decrease in infarct size [The protection of the cardiac myocyte from cell death has remained an attractive target for many therapeutic treatments for heart disease. Apoptosis, also known as programmed cell death, and necrosis play major roles in mediating ischemic injury and tissue remodeling. Thus, the possibility that cell therapy leads to protection against death of the cardiac muscle brings a new mechanism of the beneficial effects of stem cell therapy into focus. The measurement of paracrine factors from cultured stem cells as well as enhancement strategies provide evidence that stem cell-derived factors act directly to protect against cardiac myocyte cell death. Specifically, VEGF, bFGF, IGF, and SDF-1 were shown to be secreted by anoxic BMSCs, and the cell supernatants or the transplantation of these cells led to a decrease in cardiac myocyte apoptosis myocytes ,38. Furtmyocytes , and injmyocytes . In addirct size -44. In arct size . HGF hasrct size , and sperct size , intraverct size , or its rct size . Sfrp2 rrct size .Altogether, these studies demonstrate that paracrine factors from exogenously transplanted BMSCs expressing c-kit and Sca-1, or transplanted MSCs aid in prevention of cardiac myocyte cell death and, thus, in the preservation of muscle mass. However, the exact molecular pathways leading to this protection are not well defined and are likely to involve modulation of both caspase-dependent and caspase-independent pathways of cell death. This additionally discovered benefit of stem cell therapy for the treatment of the heart following injury may not be limited to cardiac myocyte protection. Since myocardial injury leads to an infiltration of inflammatory cells and upregulation of cytokines, stem cell therapy may additionally target these pathways involved in pathophysiological remodeling.et al. [in vitro co-culture of T lymphocytes from post-MI rats with isolated cardiac myocytes from a non-infarcted rat heart resulted in cytotoxicity of the cardiac myocytes. Accordingly, it is well established that MSCs play a role in suppressing adaptive immune responses. Specifically, MSCs suppressed T lymphocyte proliferation and MSCs co-cultured with purified subpopulations of immune cells altered cytokine secretion and induced a more anti-inflammatory phenotype [in vivo suppression of T lymphocyte accumulation or function may also inhibit myocardial fibrosis. Thus, alterations in the innate and adaptive immune responses in the heart by transplanted stem cells may serve as another mechanism contributing to the improvement in LV function and the attenuation of adverse LV remodelling.There are two forms of immunity, innate and adaptive. Innate immune responses are phylogenetically conserved and initiate a quick response against a pathogen or myocardial injury, whereas adaptive immune responses involve antigen recognition and subsequent antibody generation. The regulation of these two types of immune responses in the heart involves upregulation and interaction of pro-inflammatory and anti-inflammatory cytokines. In response to stress, the heart increases expression of a variety of pro-inflammatory and anti-inflammatory cytokines, which play a dual role in the heart. Initial inflammatory cytokine expression is necessary for maintaining homeostatic responses within the heart after stress or injury; however, the dysregulation and sustained upregulation of certain cytokines ultimately leads to adverse remodelling and heart failure . The speet al.  have shohenotype ,56. It ihenotype , suggest+ cells led to a decrease in collagen fiber accumulation in the infarcted region [Most of the studies using stem cell therapy after MI have shown a reduction in fibrosis. However, in most studies it was not clearly defined whether the decreased fibrosis was simply due to replacement of dead myocardium or whether the paracrine factors released from these different subpopulations of stem cells may have had direct effects on the extracellular matrix. Nevertheless, in one study, a direct effect on fibrosis by stem cells was demonstrated; MSC-conditioned medium significantly attenuated proliferation of cardiac fibroblasts and upregulated elastin, myocardin and DNA-damage inducible transcript 3 . Furtherd region . AltogetAlthough few studies have investigated a direct role of bone marrow-derived cells on cardiac myocyte contractility and bioenergetic function, it is becoming increasingly clear that paracrine factors may act via this mechanism. In one study, the intravenous injection of MSCs preserved LV systolic function after MI without decreasing infarct size, suggesting that, in this case, MSCs did not protect against cardiac myocyte death but may have had a more direct effect on cardiac myocyte contractility . FurtherAnother mechanism of cell therapy includes the ability of transplanted cells to promote endogenous repair, which may include modulation of cardiac-resident stem cells and epicardial progenitor cells by specifically regulating endogenous or stem cell-derived paracrine factors. One study demonstrated that cardiac stem cells and early committed cells expressing c-kit, MDR1, and Sca-1 express c-Met and IGF-1 receptors and synthesize and secrete corresponding ligands, HGF and IGF-1, suggesting that these factors may act in an autocrine manner to regulate the functionality of these cells . Furtherin vitro and to promote reperfusion in a mouse hind limb ischemia model appears to be dependent on HGF [Stem cells from sources other than those derived from bone marrow are also the subject of numerous investigations. For example, mesenchymal stem cells can also be isolated from adipose tissue , muscle t on HGF . In the t on HGF . As reseParacrine factors from stem cells transplanted into the myocardium play an important role in modulating LV remodeling after an ischemic injury. It should be noted that the evidence supporting this idea is based on numerous studies in animal models. The contribution of the paracrine effects in clinical trials (compared to cell intrinsic functions) cannot be exactly determined as long as autologous cells are implanted and the availability of tissue restricts information on local cytokine production. However, the clinically used cell populations, namely total bone marrow nuclear cells ,86, cultThe authors declare that they have no competing interests.JB drafted the review. SD conceived, designed, drafted, and edited the review.


Outcomes in critically ill neonates have improved over the past three decades, yet high residual mortality and morbidity rates exist. Acute kidney injury (AKI) is not just an innocent by-stander in the critically ill patient. Research on incidence and outcomes of AKI in the critically ill neonatal population is scarce. The objective of this publication is to (a) review original articles on the short- and long-term outcomes after neonatal AKI, (b) highlight key articles on adults and children with AKI in order to demonstrate how such insights might be applied to neonates, and (c) suggest clinical research studies to fill the gaps in our understanding of neonatal AKI. To date, observational studies suggest high rates of AKI and poor outcomes in critically ill neonates. Neonates with AKI are at risk of developing chronic kidney disease and hypertension. Large prospective studies are needed to test definitions and to better understand risk factors, incidence, independent outcomes, and mechanisms that lead to poor short- and long-term outcomes. Early biomarkers of AKI need to be explored in critically ill neonates. Infants with AKI need to be followed for sequelae after AKI. Advancements in neonatal–perinatal medicine have improved the survival rates of critically ill neonates, yet residual mortality and morbidity rates are significant . Acute kNovel urinary biomarkers can diagnose AKI within hours of an insult have been discovered. The original experience with several of these biomarkers occurred in neonates who required cardiopulmonary bypass surgery. Studies to detect AKI in non-cardiac critically ill neonates have not been performed. These biomarkers will change our approach to the diagnosis AKI and, hopefully, lead to better preventative and therapeutic interventions which will improve outcomes of critically ill neonates.Rodriguez et al.  showed tPublications on neonatal AKI and key pediatric and adult AKI will be used to explain our current understanding of the diagnosis, incidence, outcomes, and potential role of biomarkers in early detection of neonatal AKI. Research priorities to fill the gaps in our current understanding will be suggested.Acute kidney injury is a complex disorder that occurs with variable severity and in many clinical scenarios. Until recently, lack of universally recognized definition of AKI limited our ability to compare studies, predict clinical courses, and improve outcomes. In 2004, nephrology and critical care groups recognized these limitations and proposed an empiric working AKI definition  Table 11: The RIIn March 2007 the Acute Kidney Injury Network (AKIN), a collaborative group of investigators from all major critical care and nephrology societies, proposed a staging system which use mild AKI stage 1), moderate AKI (stage 2) and severe AKI (stage 3) in a way similar to the risk, injury and failure categories in RIFLE . The maj, moderatIn children, Akcan-Arikan et al.  proposedThese classification systems to define AKI in neonatal populations have not been performed. Large prospective studies to test these classification models in neonatal AKI are greatly needed to better understand the impact of AKI on outcomes.SCr concentrations may not change until 25–50% of the kidney function has already been lost, and, thus, it may take days before a significant rise in SCr is seen.At lower GFR, SCr will overestimate renal function due to tubular secretion of creatinine.SCr varies by muscle mass, hydration status, age and gender.Different methods (Jaffe reaction vs enzymatic) produce different values, and medications and bilirubin can affect SCr measurements by the Jaffe method , 19.Once a patient receives dialysis, SCr can no longer be used to assess kidney function, since SCr is easily dialyzed.Despite these working classification systems, the diagnosis of AKI is problematic, as current diagnoses rely on two functional abnormalities: functional changes in serum creatinine [marker of glomerular filtration rate (GFR)] and oliguria. Both these are late consequences of injury and not markers of the injury itself. The ideal marker to detect AKI should be up-regulated shortly after an injury and be independent of GFR level. SCr is the most common method to monitor renal function and to diagnose AKI, but it has significant shortcomings including:SCr in the first few days of the neonate’s life reflects the mother’s and not the infant’s renal function.2 body surface area during the first week of life to 30–40 ml/min per 1.73 m2 by 2 weeks after birth, concomitant with alterations in renal blood flow. Thereafter, GFR improves steadily over the first few months of life  and their inability to control for gestational age, birth weight, co-morbidities and severity of illness. Because of limitations in study design, one must use caution in making solid inferences about the true incidence and outcomes after neonatal AKI based on these studies.Two recent studies have explored AKI in the general critically ill neonatal population and confirm high incidences of AKI and deaths in these infants. In a retrospective analysis, Agras et al.  found a P < 0.0001 for all)  Table . RecentlOne of the most common sequelae of prematurity is the propensity to develop bronchopulmonary dysplasia (BPD), as it affects 10% and 40% of surviving very low birth weight infants and extremely low birth rate infants, respectively . The patA large prospective cohort study with accepted definitions is greatly needed to help us better understand the incidence and independent impact of AKI on asphyxiated infants, premature infants, infants undergoing cardiopulmonary bypass and the general critically ill newborn populations. The role that the kidney plays in acute and chronic pulmonary diseases in premature infants needs to be explored.Because the incidence of AKI continues to rise, while the outcomes remain poor, nephrologists and intensivists continue to devote numerous resources for the better improvement of outcomes. Recent advances in the field of early AKI biomarkers have provided great optimism. Novel urine and serum biomarkers may change our approach to this condition if they can indicate AKI hours after an insult, in comparison with the days it may take serum creatinine to rise substantially. As opposed to our current functional markers of AKI (GFR and urine output), these biomarkers promise to signal injury early in the disease process, and, hopefully, they will allow us to intervene in the disease process at the onset of acute kidney ‘injury’ as opposed to attempting to fix acute kidney ‘failure’ , 40.Biomarkers are currently being explored to differentiate between different causes of established AKI, to detect AKI early, and to prognosticate outcomes. Currently, the most promising early non-invasive biomarkers of AKI are serum and urinary neutrophil gelatinase-associated lipocalin (NGAL) , urinaryNGAL is one of the most strikingly up-regulated genes and over-expressed proteins in the kidney after ischemia [ischemia . Serum aischemia  Fig. 4)NGAL is oischemia , 51.FigLavery et al. recently examined 20 premature infants (divided into four birth weight categories with five subjects each) and looked at baseline urinary NGAL. They found that levels inversely correlated with both birth weight and gestational age. The wide baseline ranges narrowed over the course of 14 days , likely IL-18 urine levels are elevated in adults with ischemic AKI compared with other causes of renal injury, including urinary tract infection, nephrotic syndrome and chronic renal failure . IL-18 lNGAL, IL-18, KIM-1 cystatin C and many other biomarkers have been developed and are undergoing intensive testing in pediatric and adult critically ill populations. These non-invasive biomarkers of AKI need to be tested in the subsets of the critically ill neonatal population. In premature infants, baseline biomarkers may be changing during extra-uterine renal development, which will create additional challenges in the discovery of biomarkers of AKI in this population. Use of multiple markers together may better define the cause of AKI and provide information as to the time of injury. Improving our ability to diagnose AKI early in the disease process is an essential first step prior to implementing preventive and therapeutic interventions to improve outcomes.Premature infants have impaired glomerulogenesis which is more pronounced in those with acute kidney injury.Using computer assisted morphometry, Rodriguez et al. measured radial glomerular counts (RGCs) in autopsied kidneys of premature infants with short vs long survival. They obtained the RGCs by counting the layers of glomeruli, following a straight line beginning in the deepest zone of the cortex and progressing systematically to the renal capsule, in well-oriented areas. They found that premature infants who had died early during their hospitalization had lower RGCs than term infants had. Premature infants who survived to the 40-week gestational (term) age had RGCs similar to those of premature infants with shorter survival, thus suggesting that the extra-uterine environment does not allow for proper neo-glomerulogenesis. In addition, infants with AKI had lower RGCs than did similar infants without AKI, suggesting that injury during this critical time can have substantial implications for total nephron counts . RecentlThe filtration rate of single nephrons and the number of nephrons present determine total GFR. When the number of nephrons is diminished, single-nephron GFR increases as the kidney works to compensate. This compensatory hypertrophy causes the glomeruli to function under increased intracapillary hydraulic pressure, which, over time, causes damage to the capillary walls. This abnormal process leads to progressive glomerulosclerosis, proteinuria, hypertension and chronic kidney disease . The hypAlthough most survivors of AKI have improved glomerular and tubular function prior to hospital discharge, long-term renal injury has been documented in children with congenital heart diseases , Henoch–Animal models have shown a clear relationship between AKI and long-term CKD caused by damage to endothelial vascular cells progressing to fibrosis and loss of function . What isNumerous resources have been expended to improve our understanding of the pathophysiology, to test definitions and classification systems, and to develop non-invasive urinary biomarkers of AKI. Neonates have unique characteristics that challenge our ability to understand AKI in these populations and yet they are, in many ways, an ideal population to study because they lack the co-morbid and pre-existing problems that confound our understanding of how AKI affects outcomes. Because of the many shortfalls of using changes in SCr to diagnose AKI, the pediatric nephrology community needs to conduct studies to find better methods to diagnose neonatal AKI. Clear definitions which can predict hard endpoints need to be constructed. Epidemiologic studies to better understand the exact incidence and short- and long-term outcomes in this population are greatly needed. The kidneys’ role in systemic end-organ disease needs to be explored. Once these research questions have been answered, multi-center intervention studies to improve the short- and long-term outcomes in this vulnerable population can be performed.


A tendency toward bleeding often undercuts the beneficial preventive effect of higher doses of a single antithrombotic drug or combined antithrombotic therapy. Although high doses of antithrombotic drugs may be necessary for optimal prevention, such therapy can also elicit more frequent bleeding. Although major bleeding could be a reversible event is likely to lead clinicians to discontinue antithrombotic therapy which in turn could increase the risk of myocardial infarction, stroke, and cardiovascular death. Thus, to prevent thrombotic events without frequent bleeding complications, the preferred approach might be to use anti-inflammatory drugs in addition to the first-line antithrombotic drugs to reduce inflammation and thrombin formation in atheroma. Although some preliminary data have been already published, to confirm the potential benefit of anti-inflammatory drugs in acute coronary syndromes large prospective double-bind randomized trials are necessary. The hemostatic system is a physiological process to prevent hemorrhage and maintain a balance between clot formation and fluidity of blood in the circulation. After endothelial injury, platelets adhere to the exposed subendothelium and are activated by locally released agonists to stimulate thrombin formation , contribThrombin is the strongest platelet agonist, and inhibition of thrombin can also prevent platelet activation. In fact, any intervention singly directed at thrombin activity or platelet activation may simultaneously affect the other function .Aspirin , and clopidogrel, are the mainstay antiplatelet therapies for arterial disease. Together with heparin, they constitute the first-line treatments for acute coronary disease. Clinical trials have established the benefit of aspirin for coronary prevention, and it is considered the gold standard for arterial antithrombotic therapy – despite its limitations with regard to preventing thrombosis.Coadministration of aspirin and clopidogrel enhances platelet inhibition, because these agents act through different platelet receptors; however, the benefit of combined antiplatelet treatment over aspirin alone in preventing thrombotic outcomes is debated -5.Therapies that include multiple drugs affecting primary hemostasis (antiplatelet drugs) or a combination of antiplatelets and anticoagulants, as in ischemic heart disease, are more aggressive than a single therapy. Combined antithrombotic treatment confers particular risk and is associated with a higher incidence of bleeding ,7, especIn arterial thrombosis, which mainly occurs on atheroma, inflammation promotes atheroma rupture. Thus there is a need for an alternative to high doses of antithrombotic drugs and that evidence regarding the effectiveness of anti-inflammatory agents will be discussed.Current speculation is that the pathways for hemostasis may differ from the pathways of thrombosis, as it is possible to attenuate thrombosis without inhibiting hemostasis ,11.Theoretically, the risk of thrombotic events may be increased by the exposure of procoagulant tissue factor (TF) to the circulation. The presence of TF on the outer membrane is a prominent characteristic of plaque lesions. Macrophages/foam cells, smooth muscle cells, and apoptotic cells are sources of exposed TF. In patients with a disrupted atheroma that contains abundant TF, there is increased generation of surrounding thrombin. Procoagulant microparticles from stimulated and apoptotic cells may also contribute to acute thrombotic occlusion . MicropaThrombus formation is driven primarily by TF derived from the vessel wall  and circHemostasis normally occurs in minutes, and a small amount of blood-borne TF can accumulate at the site of injury. In contrast, thrombosis may occur over the course of minutes or hours, and it involves large volumes of blood flow, which permits accumulation of significant amounts of blood-borne TF.Decryption of platelet TF is linked to membrane phosphatidylserine. After undergoing the flip-flop process, platelet membrane phosphatidylserine can cause decryption of platelet TF and may contribute to local hemostasis, although the potential importance of this action is not well defined . PlateleHemostasis is a local not progressive process because clotting starts when 10–20 nmol/l of thrombin is formed; this initial thrombin activity is important for hemostasis . The locIn arterial thrombosis, which mainly occurs on atheroma, inflammation promotes atheroma rupture. In atheroma, the levels of TF, which is also expressed by monocytes and macrophage-derived foam cells, are several-fold greater than the levels in a wounded vessel . EnhanceNumerous randomized controlled trials have evaluated the effectiveness and safety of anticoagulants or antiplatelet therapy or different combinations of anticoagulant and antiplatelet therapy; or dual antiplatelet therapy were compared with aspirin in short or long-term thrombosis prevention studies.In a dose-ranging trial of enoxaparin 1.25 mg/kg and 1.0 mg/kg (every 12 hr) in patients with unstable angina, the incidence of death, recurrent myocardial infarction, or recurrent ischemia requiring revascularization was 5.6% with the higher dose and 5.2% with the lower dose . Major hMelagatran and dabigatran are active antithrombin drugs that selectively and competitively inhibit free and clot-bound thrombin. After oral administration, ximelagatran is absorbed and biotransformed to melagatran, the dominant compound in plasma. In a dose-ranging study comparing melagatran/ximelagatran to the low molecular weight dalteparin, the highest dose of ximelagatran had better clinical efficacy and a nonsignificant tendency toward a greater transfusion volume in hip replacement patients . AlthougAnother study reported that total bleeding (major and minor) was lower with ximelagatran versus warfarin in atrial fibrillation patients . HoweverIn dose-ranging studies with dabigatran, another active antithrombin drug, in patients undergoing hip or knee surgery , there wA dose-ranging study of BAY 59-7939 (Rivaroxaban), a direct oral inhibitor of activated Factor X, was performed with total knee replacement patients . Among tA third dose-ranging study with BAY 59-7939 administered as a single daily dose was recently published . ResultsTaken together, the results of dose-finding studies of BAY 59-7939 lead to an interesting observation: it appears that higher doses increase the frequency of major postoperative bleeding events and are less effective in preventing venous thromboembolism compared to moderate doses. This could be by chance or because the anti-thrombotic effect is related to the strongest in situ inhibition of thrombin generated in the damaged vessel wall, which prevents local activation of protein C/thrombomodulin. The protein C anticoagulant pathway is a major system for controlling thrombosis and inflammation .Thrombin binds to thrombomodulin and then activates protein C approximately 1000 times faster than free thrombin. Activated protein C proteolytically inactivates clotting factor Va and factor VIIIa, thereby blocking the amplification of the coagulation system .Although thrombin increases protein C activation by binding to endothelial thrombomodulin, in atheroma, inflammation might overwhelm protective anticoagulant forces . InadequThe hypothesis that strong inhibition of thrombin could causes adverse outcomes is consistent with the physiological importance of activated protein C in the protein C anticoagulant pathway and in the control of the innate inflammatory response and because clinical studies reveal that deficiencies of protein C lead to microvascular thrombosis ,33.During treatment with antithrombotic drugs, in the presence of a wounded vessel, the relatively small amount of thrombin generated in situ is also inhibited by therapy. This can affect hemostasis with the potential consequence of bleeding and, although major bleeding could be a reversible event, antithrombotic therapy must be stopped which in turn could increase the risk of arterial thrombosis and death .Platelets also play a central role in initiating and propagating pathological thrombosis.Antiplatelet therapy is important in the management of acute coronary syndromes after spontaneous plaque disruption or mechanical disruption caused by percutaneous coronary intervention. Aspirin is the gold standard for prevention of acute myocardial syndromes, but higher dosages of aspirin do not provide better protection from events and are associated with increased risks of gastrointestinal bleeding .The CURE trial  investig12 ADP receptor antagonist prasugrel, in patients undergoing elective or urgent percutaneous coronary intervention. Patients were treated with a low dose (40 mg loading dose followed by 7.5 mg daily), an intermediate dose (60 mg loading dose followed by 10 mg daily), or a high dose (60 mg loading dose followed by 15 mg daily) of prasugrel or clopidogrel. Among prasugrel-treated patients, there were no group differences in the frequency of major adverse coronary events, although at 30 days myocardial infarction was less frequent in the high-dose group. At 30 days there was a trend toward a higher incidence of the composite of major, minor, or minimal bleeding for the high-dose prasugrel group (5.1%) compared to the intermediate and low-dose groups (3.5% with each). As expected, the vascular access site was the most frequent site of bleeding [The JUMBO-TIMI 26 trial  investigbleeding . The JUMThe reviewed studies suggest that when comparing low and high doses of antithrombotic drugs there is a strong dose-relationship regarding the capacity to prevent arterial thrombosis, but there is only a weak dose-relationship when comparing intermediate and high doses. However, there was a clear dose-related effect on bleeding risk in all trials. Thus, the highest doses of antithrombotic drugs yield the most frequent bleeding without providing the greatest level of prevention.At present, there is agreement that vessel wall inflammation is a major factor in the development of atherosclerosis, atheroma instability, and plaque disruption, events that are followed by local thrombosis, which underlies the clinical presentation of acute coronary syndromes. Inflammation is a reflexive response to mechanical irritation, or injury, and although restricted inflammation is beneficial, persistent inflammation incites tissue destruction . In healIn agreement with this, there is evidence that blocking inflammation can prevent thrombosis and acute coronary events. For example Versaci et al.  reportedGlucocorticoids can have rapid effects on inflammation but prolonged or high-dose glucocorticoid therapy has multiple side effects .Altman et al. Table 33 reporteThere is accumulating evidence that the lipid-independent effects of cholesterol-lowering drugs are also relevant to the management of acute coronary syndromes. Statins exert a number of pleiotropic effects, including improvement of endothelial function, stabilization of atherosclerotic plaques, and inhibition of inflammatory responses. The anti-inflammatory effects of statins may have a clinical impact on vascular and nonvascular conditions such as multiple sclerosis and rheumatoid arthritis -50. PretAtherothrombotic complications develop as a result of atherosclerosis in one or more coronary, cerebrovascular, or peripheral arteries. Is the thrombin generated in a disrupted atheroma similar in all patients? In the same patient is the thrombin generated in an inflamed plaque and a culprit lesion similar? Why are diabetic patients more resistant to the effects of antiplatelet drugs than are nondiabetic patients? .Based on the differences in the mechanisms underlying hemostasis and thrombosis, a practical point can be made regarding antithrombotic therapies. Although increased concentrations of antithrombotic drugs will affect both thrombosis and hemostasis, because thrombin generated in hemostasis is lower than in thrombosis, any increase in anticoagulant potential will produce a tendency toward bleeding . Therefo2, producing an imbalance in hemostatic prostanoids that might increase the risk for thrombotic cardiovascular events [2 by the concomitant use of aspirin might offset the prothrombotic effect of selective COX-2 inhibitor. and other NSAID-related MI risk.However, in 2001, Mukherjee et al.  recommenr events ,57. ReduAs mentioned above, preliminary data from our randomized controlled trial of the preferential COX-2 inhibitor meloxicam in patients with acute coronary syndrome who were treated with aspirin demonstrated a statistically significant reduction in cardiovascular events  and no cVery recently Koo et al. present the report on the use of the COX-2 inhibitor celecoxib, to reduce restenosis of patients underwent coronary angioplasty. After 6 months paclitaxel-eluting stent implantation mean in-stent late luminal loss was lower in the celecoxib group  than in the control group . Also celecoxib reduced the need for revascularisation of the target lesion .In conclusion, the beneficial preventive effect of high doses of a single antithrombotic drug or combined antithrombotic therapy could be overcome by the tendency toward bleeding. and there is a dose-related association between bleeding and death . DetermiThus, the preferred approach might be to use anti-inflammatory drugs in addition to antithrombin drugs and aspirin to reduce inflammation and thrombin formation in atheroma. Although some preliminary data have been already published, in acute coronary syndromes large prospective double-bind randomized trials are necessary to confirm the potential benefit of this treatment.