Smad3 Signaling Promotes Fibrosis While Preserving Cardiac and Aortic Geometry in Obese Diabetic Mice.

BACKGROUND: Heart failure in diabetics is associated with cardiac hypertrophy, fibrosis and diastolic dysfunction. Activation of transforming growth factor-ß/Smad3 signaling in the diabetic myocardium may mediate fibrosis and diastolic heart failure, while preserving matrix homeostasis. We hypothesized that Smad3 may play a key role in the pathogenesis of cardiovascular remodeling associated with diabetes mellitus and obesity. METHODS AND RESULTS: We generated leptin-resistant db/db Smad3 null mice and db/db Smad3+/- animals. Smad3 haploinsufficiency did not affect metabolic function in db/db mice, but protected from myocardial diastolic dysfunction, while causing left ventricular chamber dilation. Improved cardiac compliance and chamber dilation in db/db Smad3+/- animals were associated with decreased cardiomyocyte hypertrophy, reduced collagen deposition, and accentuated matrix metalloproteinase activity. Attenuation of hypertrophy and fibrosis in db/db Smad3+/- hearts was associated with reduced myocardial oxidative and nitrosative stress. db/db Smad3 null mice had reduced weight gain and decreased adiposity associated with attenuated insulin resistance, but also exhibited high early mortality, in part, because of spontaneous rupture of the ascending aorta. Ultrasound studies showed that both lean and obese Smad3 null animals had significant aortic dilation. Aortic dilation in db/db Smad3 null mice occurred despite reduced hypertension and was associated with perturbed matrix balance in the vascular wall. CONCLUSIONS: Smad3 mediates diabetic cardiac hypertrophy, fibrosis, and diastolic dysfunction, while preserving normal cardiac geometry and maintaining the integrity of the vascular wall.

Selecting an oral anticoagulant for patients with nonvalvular atrial fibrillation.

While the use of warfarin has been the cornerstone of thromboembolism prevention in patients with atrial fibrillation (AF), its limitations have led to the introduction of a new generation of direct-acting oral anticoagulants. Evidence from large phase III clinical trials, observational studies and pharmacokinetic analyses can guide clinicians to select the most effective and safest form of anticoagulation for patients with nonvalvular AF. This manuscript describes the main pharmacologic, clinical and epidemiological characteristics of each new oral anticoagulant and their use in selected clinical scenarios, including patients with: advanced age; at low or high risk of stroke; potential drug-drug interactions; on concomitant antiplatelet therapy; at high risk for acute coronary syndrome; with recent gastrointestinal bleeding; with renal impairment; and with hepatic dysfunction.

CXCR3-independent actions of the CXC chemokine CXCL10 in the infarcted myocardium and in isolated cardiac fibroblasts are mediated through proteoglycans.

AIMS: The CXC chemokine CXCL10 is up-regulated in the infarcted myocardium and limits cardiac fibrosis by inhibiting growth factor-mediated fibroblast migration. CXCL10 signals by binding to its receptor CXCR3; however, recently CXCR3-independent CXCL10 actions have been suggested. Our study explores the role of CXCR3 signalling in myocardial infarction and investigates its involvement in mediating the anti-fibrotic effects of CXCL10. METHODS AND RESULTS: Wild-type and CXCR3 null mice underwent reperfused infarction protocols. CXCL10 was markedly induced in the infarct; in contrast, expression of the other two CXCR3 ligands, CXCL9 and CXCL11 was extremely low. CXCR3 loss did not affect scar size, geometric ventricular remodelling, collagen deposition, and systolic dysfunction of the infarcted heart. CXCR3 null mice had increased peak neutrophil recruitment and delayed myofibroblast infiltration in the infarcted heart, but exhibited comparable myocardial expression of pro-inflammatory cytokines and chemokines. In vitro, CXCL10 did not modulate Transforming Growth Factor (TGF)-ß signalling, but inhibited basic fibroblast growth factor (bFGF)-induced cardiac fibroblast migration in both wild-type and CXCR3 null cells. Treatment of fibroblasts with heparinase and chondroitinase to cleave glycosaminoglycan chains abrogated the inhibitory effects of CXCL10 on cell migration. CONCLUSION: CXCR3 signalling does not critically regulate cardiac remodelling and dysfunction following myocardial infarction. The anti-fibrotic effects of CXCL10 in the healing infarct and in isolated cardiac fibroblasts are CXCR3-independent and may be mediated through proteoglycan signalling. Thus, administration of CXCR3-defective forms of CXCL10 may be an effective anti-fibrotic strategy in the remodelling myocardium without activating a potentially injurious, CXCR3-driven T cell response.

Comparison of the phase III clinical trial designs of novel oral anticoagulants versus warfarin for the treatment of nonvalvular atrial fibrillation: implications for clinical practice.

Although vitamin K antagonists (VKAs) have been the backbone of thromboprophylaxis in nonvalvular atrial fibrillation, their limitations have encouraged the development of a new generation of oral anticoagulants. This review compares the different designs and procedures used to conduct four phase III trials that tested dabigatran, rivaroxaban, apixaban, and edoxaban versus VKAs. Although pharmacologic characteristics and results of the main trials are briefly discussed, this review mainly focuses on study designs, enrollment criteria, populations studied, quality metrics, and transition strategies between oral anticoagulants. While each of the trials was of high quality, performed independently, and led by independent academic groups, substantial differences exist in terms of drug pharmacology and trial characteristics. Caution is advised when comparing results across trials as practicing clinicians strive to personalize anticoagulation treatments for their individual patients. We believe that the differences in the pharmacokinetic and pharmacodynamic profiles of the available novel oral anticoagulants (NOACs), coupled with substantial heterogeneity in the trial populations and designs and procedures used to conduct the trials, support an important role for each of the NOACs dependent upon the specific clinical scenario faced by the practicing clinician.

Computed tomography and echocardiography in patients with acute pulmonary embolism: part 1: correlation of findings of right ventricular enlargement.

PURPOSE: To evaluate the correlation between the computed tomography (CT)-derived right ventricle (RV) to left ventricle (LV) diameter ratio and the RV size determined by echocardiography in patients with acute pulmonary embolism. MATERIALS AND METHODS: Consecutive CT pulmonary angiography examinations (August 2003 to May 2010) from a single, large, urban teaching hospital were retrospectively reviewed. For a cohort of 777 subjects who underwent echocardiography within 48 hours of the CT acquisition, the qualitative RV size (divided into 5 categories) extracted from the echocardiography report was correlated with the CT-derived RV/LV diameter ratio. RESULTS: There was moderate correlation (Spearman rank correlation coefficient=0.54, P<0.001) between the CT-derived RV/LV ratio and the RV size as determined by echocardiography. The correlation coefficient and the concordance rate were inversely related to the time difference between the acquisitions of the 2 modalities. CONCLUSIONS: CT and echocardiography findings to assess the RV size after acute pulmonary embolism have moderate correlation.

Computed tomography and echocardiography in patients with acute pulmonary embolism: part 2: prognostic value.

PURPOSE: The aim of the study was to compare the prognostic value of right ventricular (RV) dysfunction detected on computed tomography pulmonary angiography (CTPA) and transthoracic echocardiography (TTE) in patients with acute pulmonary embolism (PE). MATERIALS AND METHODS: From all consecutive CTPAs performed between August 2003 and May 2010 that were positive for acute PE (n=1744), those with TTE performed within 48 hours of CTPA (n=785) were selected as the study cohort. Multivariate logistic regression analysis was performed to assess the association of CTPA RV/left ventricular (LV) diameter ratio and TTE RV strain with PE-related 30-day mortality, including other associated factors as covariates. The predictive ability (area under the curve) was compared between the model including the CT RV/LV diameter ratio and that including TTE RV strain. Test characteristics of the 2 modalities were calculated. RESULTS: Both CT RV/LV diameter ratio and TTE RV strain were independently associated with PE-related 30-day mortality (adjusted odds ratio=1.14, P=0.023 for 0.1 increment of the CT RV/LV diameter ratio; and odds ratio=2.13, P=0.041 for TTE RV strain). History of congestive heart failure and malignancy were independent predictors of PE-related mortality, while there was significantly lower mortality associated with anticoagulation use. The model including TTE RV strain and that including CT RV/LV had similar predictive ability (area under the curve=0.80 vs. 0.81, P=0.50). The sensitivity, specificity, and positive and negative predictive values of TTE RV strain and CT RV/LV diameter ratio at a cutoff of ≥1.0 were similar for PE-related 30-day mortality. CONCLUSIONS: Both RV strain on TTE and an increased CT RV/LV diameter ratio are predictors of PE-related 30-day mortality with similar prognostic significance.

Thrombospondin-1 induction in the diabetic myocardium stabilizes the cardiac matrix in addition to promoting vascular rarefaction through angiopoietin-2 upregulation.

RATIONALE: Diabetes mellitus is associated with cardiac fibrosis. Matricellular proteins are induced in fibrotic conditions and modulate fibrogenic and angiogenic responses by regulating growth factor signaling. OBJECTIVE: Our aim was to test the hypothesis that the prototypical matricellular protein thrombospondin (TSP)-1, a potent angiostatic molecule and crucial activator of transforming growth factor-ß, may play a key role in remodeling of the diabetic heart. METHODS AND RESULTS: Obese diabetic db/db mice exhibited marked myocardial TSP-1 upregulation in the interstitial and perivascular space. To study the role of TSP-1 in remodeling of the diabetic heart, we generated and characterized db/db TSP-1(-/-) (dbTSP) mice. TSP-1 disruption did not significantly affect weight gain and metabolic function in db/db animals. When compared with db/db animals, dbTSP mice had increased left ventricular dilation associated with mild nonprogressive systolic dysfunction. Chamber dilation in dbTSP mice was associated with decreased myocardial collagen content and accentuated matrix metalloproteinase-2 and -9 activity. TSP-1 disruption did not affect inflammatory gene expression and activation of transforming growth factor-ß/small mothers against decapendaplegic signaling in the db/db myocardium. In cardiac fibroblasts populating collagen pads, TSP-1 incorporation into the matrix did not activate transforming growth factor-ß responses, but inhibited leptin-induced matrix metalloproteinase-2 activation. TSP-1 disruption abrogated age-associated capillary rarefaction in db/db mice, attenuating myocardial upregulation of angiopoietin-2, a mediator that induces vascular regression. In vitro, TSP-1 stimulation increased macrophage, but not endothelial cell, angiopoietin-2 synthesis. CONCLUSIONS: TSP-1 upregulation in the diabetic heart prevents chamber dilation by exerting matrix-preserving actions on cardiac fibroblasts and mediates capillary rarefaction through effects that may involve angiopoietin-2 upregulation.

Thrombospondin-1 regulates adiposity and metabolic dysfunction in diet-induced obesity enhancing adipose inflammation and stimulating adipocyte proliferation.

As a typical matricellular protein, thrombospondin (TSP)-1, binds to the structural matrix and regulates cellular behavior by modulating growth factor and cytokine signaling. Obesity and diabetes are associated with marked upregulation of TSP-1 in adipose tissue. We hypothesized that endogenous TSP-1 may play an important role in the pathogenesis of diet-induced obesity and metabolic dysfunction. Accordingly, we examined the effects of TSP-1 gene disruption on weight gain, adiposity, and adipose tissue inflammation in mice receiving a high-fat diet (HFD: 60% fat, 20% carbohydrate) or a high-carbohydrate low-fat diet (HCLFD: 10% fat, 70% carbohydrate). HFD mice had significantly higher TSP-1 expression in perigonadal adipose tissue; TSP-1 was predominantly localized in the adipose interstitium. TSP-1 loss attenuated weight gain and fat accumulation in HFD and HCLFD groups. Compared with corresponding wild-type animals, TSP-1-null mice had decreased insulin levels but exhibited elevated free fatty acid and triglyceride levels, suggesting impaired fatty acid uptake. TSP-1 loss did not affect adipocyte size and had no effect on adipose vascular density. However, TSP-1-null mice exhibited attenuated tumor necrosis factor-α mRNA expression and reduced macrophage infiltration, suggesting a role for TSP-1 in mediating obesity-associated inflammation. In vitro, TSP-1 enhanced proliferation of 3T3-L1 preadipocytes but did not modulate inflammatory cytokine and chemokine synthesis. In conclusion, TSP-1 upregulation contributes to weight gain, adipose growth, and the pathogenesis of metabolic dysfunction. The effects of TSP-1 may involve stimulation of adipocyte proliferation, activation of inflammatory signaling, and facilitated fatty acid uptake by adipocytes.

Systematic characterization of myocardial inflammation, repair, and remodeling in a mouse model of reperfused myocardial infarction.

Mouse models of myocardial infarction are essential tools for the study of cardiac injury, repair, and remodeling. Our current investigation establishes a systematic approach for quantitative evaluation of the inflammatory and reparative response, cardiac function, and geometry in a mouse model of reperfused myocardial infarction. Reperfused mouse infarcts exhibited marked induction of inflammatory cytokines that peaked after 6 hr of reperfusion. In the infarcted heart, scar contraction and chamber dilation continued for at least 28 days after reperfusion; infarct maturation was associated with marked thinning of the scar, accompanied by volume loss and rapid clearance of cellular elements. Echocardiographic measurements of end-diastolic dimensions correlated well with morphometric assessment of dilative remodeling in perfusion-fixed hearts. Hemodynamic monitoring was used to quantitatively assess systolic and diastolic function; the severity of diastolic dysfunction following myocardial infarction correlated with cardiomyocyte hypertrophy and infarct collagen content. Expression of molecular mediators of inflammation and cellular infiltration needs to be investigated during the first 72 hr, whereas assessment of dilative remodeling requires measurement of geometric parameters for at least four weeks after the acute event. Rapid initiation and resolution of the inflammatory response, accelerated scar maturation, and extensive infarct volume loss are important characteristics of infarct healing in mice.

Endogenous thrombospondin 1 protects the pressure-overloaded myocardium by modulating fibroblast phenotype and matrix metabolism.

The matricellular protein thrombospondin (TSP) 1 is induced after tissue injury and may regulate reparative responses by activating transforming growth factor-ß, by suppressing angiogenesis and by modulating inflammation and matrix metabolism. We hypothesized that endogenous TSP-1 may be involved in the pathogenesis of cardiac remodeling in the pressure-overloaded heart. Myocardial TSP-1 expression was increased in a mouse model of pressure overload because of transverse aortic constriction. TSP-1(-/-) mice exhibited increased early hypertrophy and enhanced late dilation in response to pressure overload. Pressure-overloaded TSP-1 null mice had intense degenerative cardiomyocyte changes, exhibiting more extensive sarcomeric loss and sarcolemmal disruption when compared with wild-type hearts. Accentuated hypertrophy and cardiomyocyte injury in TSP-1(-/-) hearts was accompanied by increased myofibroblast density. However, despite a 2-fold higher infiltration of the cardiac interstitium with myofibroblasts, pressure-overloaded TSP-1 null hearts did not exhibit significantly increased collagen content when compared with wild-type hearts. The disproportionately low collagen content in TSP-1 null hearts was attributed to infiltration with abundant, but functionally defective, fibroblasts that exhibited impaired myofibroblast differentiation and reduced collagen expression in comparison with wild-type fibroblasts. Impaired myofibroblast activation in TSP-1 null hearts was associated with reduced Smad2 phosphorylation reflecting defective transforming growth factor-ß signaling. Moreover, TSP-1 null hearts had increased myocardial matrix metalloproteinase 3 expression and enhanced matrix metalloproteinase 9 activation after pressure overload. TSP-1 upregulation in the pressure-overloaded heart critically regulates fibroblast phenotype and matrix remodeling by activating transforming growth factor-ß signaling and by promoting matrix preservation, thus preventing chamber dilation.

Smad3 signaling critically regulates fibroblast phenotype and function in healing myocardial infarction.

RATIONALE: Cardiac fibroblasts are key effector cells in the pathogenesis of cardiac fibrosis. Transforming growth factor (TGF)-beta/Smad3 signaling is activated in the border zone of healing infarcts and induces fibrotic remodeling of the infarcted ventricle contributing to the development of diastolic dysfunction. OBJECTIVE: The present study explores the mechanisms responsible for the fibrogenic effects of Smad3 by dissecting its role in modulating cardiac fibroblast phenotype and function. METHODS AND RESULTS: Smad3 null mice and corresponding wild-type controls underwent reperfused myocardial infarction protocols. Surprisingly, reduced collagen deposition in Smad3-/- infarcts was associated with increased infiltration with myofibroblasts. In vitro studies demonstrated that TGF-beta1 inhibited murine cardiac fibroblast proliferation; these antiproliferative effects were mediated via Smad3. Smad3-/- fibroblasts were functionally defective, exhibiting impaired collagen lattice contraction when compared with wild-type cells. Decreased contractile function was associated with attenuated TGF-beta-induced expression of alpha-smooth muscle actin. In addition, Smad3-/- fibroblasts had decreased migratory activity on stimulation with serum, and exhibited attenuated TGF-beta1-induced upregulation of extracellular matrix protein synthesis. Upregulation of connective tissue growth factor, an essential downstream mediator in TGF-beta-induced fibrosis, was in part dependent on Smad3. Connective tissue growth factor stimulation enhanced extracellular matrix protein expression by cardiac fibroblasts in a Smad3-independent manner. CONCLUSIONS: Disruption of Smad3 results in infiltration of the infarct with abundant hypofunctional fibroblasts that exhibit impaired myofibroblast transdifferentiation, reduced migratory potential, and suppressed expression of fibrosis-associated genes.

CCR5 signaling suppresses inflammation and reduces adverse remodeling of the infarcted heart, mediating recruitment of regulatory T cells.

Myocardial infarction triggers an inflammatory reaction that is involved in cardiac remodeling. Cardiac repair is dependent on regulatory mechanisms that suppress inflammation and prevent excessive matrix degradation. Chemokine induction in the infarcted heart mediates recruitment of leukocyte subsets with distinct properties. We demonstrate that signaling through the CC chemokine receptor 5 (CCR5) prevents uncontrolled postinfarction inflammation and protects from adverse remodeling by recruiting suppressive mononuclear cells. CCR5 and its ligands macrophage inflammatory protein (MIP)-1alpha and MIP-1beta were markedly induced in the infarcted mouse myocardium. In addition, almost 40% of the mononuclear cells infiltrating the infarct expressed CCR5. CCR5(-/-) mice exhibited marked upregulation of proinflammatory cytokine and chemokine expression in the infarct. In wild-type infarcts CCR5+ mononuclear cells had anti-inflammatory properties, expressing higher levels of IL-10 than CCR5- cells. In contrast, mononuclear cells isolated from CCR5(-/-) infarcts had reduced IL-10 expression. Moreover, enhanced inflammation in the absence of CCR5 was associated with impaired recruitment of CD4+/foxp3+ regulatory T cells (Tregs). The CCR5+ Treg subset exhibited increased IL-10 expression, reflecting potent anti-inflammatory activity. Accentuated inflammation in CCR5(-/-) infarcts was associated with increased matrix metalloproteinase (MMP) expression, reduced TIMP levels, and enhanced MMP-2 and MMP-9 activity, resulting in worse cardiac dilation. These results suggest that CCR5-mediated Treg recruitment may restrain postinfarction inflammation, preventing excessive matrix degradation and attenuating adverse remodeling.

The extracellular matrix as a modulator of the inflammatory and reparative response following myocardial infarction.

The dynamic alterations in the cardiac extracellular matrix following myocardial infarction not only determine the mechanical properties of the infarcted heart, but also directly modulate the inflammatory and reparative response. During the inflammatory phase of healing, rapid activation of Matrix Metalloproteinases (MMP) causes degradation of the cardiac extracellular matrix. Matrix fragments exert potent pro-inflammatory actions, while MMPs process cytokines and chemokines altering their biological activity. In addition, vascular hyperpermeability results in extravasation of fibronectin and fibrinogen leading to formation of a plasma-derived provisional matrix that serves as a scaffold for leukocyte infiltration. Clearance of the infarct from dead cells and matrix debris is essential for resolution of inflammation and marks the transition to the proliferative phase. The fibrin-based provisional matrix is lysed and cellular fibronectin is secreted. ED-A fibronectin, mechanical tension and Transforming Growth Factor (TGF)-beta are essential for modulation of fibroblasts into myofibroblasts, the main collagen-secreting cells in the wound. The matricellular proteins thrombospondin-1 and -2, osteopontin, tenascin-C, periostin, and secreted protein acidic and rich in cysteine (SPARC) are induced in the infarct regulating cellular interactions and promoting matrix organization. As the infarct matures, matrix cross-linking results in formation of a dense collagen-based scar. At this stage, shielding of fibroblasts from external mechanical tension by the mature matrix network may promote deactivation and cellular quiescence. The components of the extracellular matrix do not passively follow the pathologic alterations of the infarcted heart but critically modulate inflammatory and reparative pathways by transducing signals that affect cell survival, phenotype and gene expression.

Induction of the CXC chemokine interferon-gamma-inducible protein 10 regulates the reparative response following myocardial infarction.

RATIONALE: Interferon-gamma-inducible protein (IP)-10/CXCL10, an angiostatic and antifibrotic chemokine with an important role in T-cell trafficking, is markedly induced in myocardial infarcts, and may regulate the reparative response. OBJECTIVE: To study the role of IP-10 in cardiac repair and remodeling. METHODS AND RESULTS: We studied cardiac repair in IP-10-null and wild-type (WT) mice undergoing reperfused infarction protocols and examined the effects of IP-10 on cardiac fibroblast function. IP-10-deficient and WT animals had comparable acute infarct size. However, the absence of IP-10 resulted in a hypercellular early reparative response and delayed contraction of the scar. Infarcted IP-10(-/-) hearts exhibited accentuated early dilation, followed by rapid wall thinning during infarct maturation associated with systolic dysfunction. Although IP-10-null and WT mice had comparable cytokine expression, the absence of IP-10 was associated with marked alterations in the cellular content of the infarct. IP-10(-/-) infarcts had more intense infiltration with CD45(+) leukocytes, Mac-2(+) macrophages, and alpha-smooth muscle actin (alpha-SMA)(+) myofibroblasts than WT infarcts but exhibited reduced recruitment of the subpopulations of leukocytes, T lymphocytes and alpha-SMA(+) cells that expressed CXCR3, the IP-10 receptor. IP-10 did not modulate cardiac fibroblast proliferation and apoptosis but significantly inhibited basic fibroblast growth factor-induced fibroblast migration. In addition, IP-10 enhanced growth factor-mediated wound contraction in fibroblast-populated collagen lattices. CONCLUSIONS: Endogenous IP-10 is an essential inhibitory signal that regulates the cellular composition of the healing infarct and promotes wound contraction, attenuating adverse remodeling. IP-10-mediated actions may be due, at least in part, to direct effects on fibroblast migration and function.

Monocyte chemoattractant protein-1/CCL2 as a biomarker in acute coronary syndromes.

The CC chemokine monocyte chemoattractant protein (MCP)-1/CCL2 is involved in the formation, progression, and destabilization of atheromatous plaques and plays an essential role in postinfarction remodeling. These properties generated significant interest in the potential significance of MCP-1 as a biomarker in acute coronary syndromes (ACS). Emerging evidence suggests that MCP-1 plasma levels have prognostic value in the acute and chronic phase following ACS, providing information independent of standard clinical variables. The mechanisms responsible for adverse prognosis in patients with elevated plasma MCP-1 following ACS remain unknown. High plasma MCP-1 levels may reflect a higher burden of atherosclerotic disease, may exert prothrombotic effects resulting in recurrent coronary events, or may identify patients who mount a more intense cardiac inflammatory reaction following a coronary event, resulting in enhanced adverse remodeling. Beyond its prognostic significance, the MCP-1 axis may be an attractive target for therapy in patients with ACS.

Left main coronary artery stenosis treatment with two paclitaxel-eluting stents in a patient with cardiac allograft vasculopathy / Tratamiento de una estenosis del tronco de la coronaria izquierda con dos stents liberadores de paclitaxel en un paciente con vasculopatía coronaria postrasplante

Cardiac transplantation is a well defined therapy for end stage heart failure. After the first year of transplantation, allograft coronary artery disease (ACAD) is the second main cause of death. The ACAD is defined as a diffuse process affecting the entire length of epicardial vessels. Once ACAD has been established, treatments such as coronary angioplasty, coronary stenting, and coronary bypass are performed. We present a case of successful stenting of the left main coronary artery (LMCA) in a patient with ACAD. The patient's medical history was significant for heart transplantation due to ischemic heart failure. Four years after transplantation the patient was admitted again due to sudden worsening of New York Heart Association functional class and extreme fatigue. Coronary angiogram showed a severe stenosis in the proximal segment of the LMCA; we performed stenting with a paclitaxel-eluting stent (PES). Six months after the procedure, the patient had an elective angiogram, where we discovered a new severe occlusion distally to the former stent; a second PES was implanted. Fourteen months after the second stenting, a new elective angiogram was performed without evidence of in-stent restenosis. After a 8-year follow-up since transplantation, the patient is free from dyspnea, angina, and adverse cardiovascular events. Our report suggests the efficacy of PES as ACAD treatment of the unprotected LMCA.

No association found between the insertion/deletion of a 287-bp alu repeat sequence within intron 16 of the angiotensin-I-converting enzyme (ACE) gene in Mexican patients and binary restenosis after coronary stenting.

BACKGROUND: It has been suggested that the incidence of coronary restenosis after a percutaneous coronary intervention is much higher in patients with a 287-bp alu repeat sequence within intron 16 of the angiotensin-I-converting enzyme (ACE) gene (deletion allele) than in others, but published studies are conflicting. METHODS: The presence (insertion) or absence (deletion) of a 287-bp alu repeat sequence within intron 16 of the ACE gene (I/D polymorphism) was analyzed by polymerase chain reaction in a group of 168 patients with coronary artery disease who underwent coronary artery stenting. Basal and procedure coronary angiographies were analyzed searching for angiographic predictors of restenosis and follow-up angiography was analyzed looking for binary restenosis. RESULTS: Distribution of angiotensin converting enzyme I/D polymorphisms was similar in patients with and without restenosis. Similar results were observed when the analysis was made considering the type of stent implanted. On the other hand, the whole group of coronary artery disease patients showed increased frequencies of the D allele (p=0.00001, OR=2.17, 95% CI=1.49-3.16) and ID genotype (p=0.0002, OR=2.58, 95%CI=1.49-4.47) when compared to healthy controls. CONCLUSIONS: Genetic variations of the ACE gene could be a genetic factor related to coronary artery disease in the Mexican mixed racial ancestry individuals, but do not support its role as a risk factor for developing restenosis after coronary stenting.

The interleukin 1B-511 polymorphism is associated with the risk of developing restenosis after coronary stenting in Mexican patients.

Inflammation is the primary response to vessel wall injury caused by stent placement in coronary arteries. Cytokines of the interleukin-1 family are central regulators in immunoinflammatory mechanisms. The objective of this study was to test for association between IL-1 family gene polymorphisms and risk for restenosis after coronary stent placement. The IL-1B-511, IL-1F10.3, RN.4T>C, RN.6/1C>T, RN.6/2C>G, and IL-1RN VNTR polymorphisms were analyzed by 5' exonuclease TaqMan genotyping assays and polymerase chain reaction in a group of 165 patients who underwent coronary artery stenting. Basal and procedure coronary angiography were analyzed in search of angiographic predictors of restenosis and follow-up angiography was analyzed in search of binary restenosis. Patients with IL-1B-511 TT genotype had a 1.89-fold increased risk of developing restenosis. The analysis considering the lesions treated demonstrated that the lesions of patients with IL-1B-511 TT genotype had a 3.44-fold increased risk of developing restenosis. When the analysis considered the type of stent, the risk of developing restenosis was increased in lesions of patients with TT genotype (odds ratio = 4.50) who underwent coronary bare-metal stent implantation. Multiple logistic analysis identified IL-1B-511 TT genotype as an independent predictor for restenosis. The results suggest that IL-1B-511 polymorphism could be involved in the risk of developing restenosis after coronary stent placement.