Macrophage activation by heparanase is mediated by TLR-2 and TLR-4 and associates with plaque progression.

OBJECTIVE: Factors and mechanisms that activate macrophages in atherosclerotic plaques are incompletely understood. We examined the capacity of heparanase to activate macrophages. METHODS AND RESULTS: Highly purified heparanase was added to mouse peritoneal macrophages and macrophage-like J774 cells, and the levels of tumor necrosis factor-α, matrix metalloproteinase-9, interlukin-1, and monocyte chemotactic protein-1 were evaluated by ELISA. Gene expression was determined by RT-PCR. Cells collected from Toll-like receptor-2 and Toll-like receptor-4 knockout mice were evaluated similarly. Heparanase levels in the plasma of patients with acute myocardial infarction, stable angina, and healthy subjects were determined by ELISA. Immunohistochemistry was applied to detect the expression of heparanase in control specimens and specimens of patients with stable angina or acute myocardial infarction. Addition or overexpression of heparanase variants resulted in marked increase in tumor necrosis factor-α, matrix metalloproteinase-9, interlukin-1, and monocyte chemotactic protein-1 levels. Mouse peritoneal macrophages harvested from Toll-like receptor-2 or Toll-like receptor-4 knockout mice were not activated by heparanase. Plasma heparanase level was higher in patients with acute myocardial infarction, compared with patients with stable angina and healthy subjects. Pathologic coronary specimens obtained from vulnerable plaques showed increased heparanase staining compared with specimens of stable plaque and controls. CONCLUSIONS: Heparanase activates macrophages, resulting in marked induction of cytokine expression associated with plaque progression toward vulnerability.

Enhancing Sweat Rate Using a Novel Device for the Treatment of Congestion in Heart Failure.

BACKGROUND: Current treatment of fluid retention in heart failure relies primarily on diuretics. However, adequate decongestion is not achieved in many patients. We aimed to study the feasibility and short-term performance of a novel approach to remove fluids and sodium directly from the interstitial compartment by enhancing sweat rate. METHODS: We used a device designed to enhance fluid and salt loss via the eccrine sweat glands. Skin temperature in the lower body was increased from 35 °C to 38 °C, where the slope of the relationship between temperature and sweat production is linear. The sweat evaporates instantaneously, thus avoiding the awareness of perspiration. The primary efficacy endpoint was the ability to increase skin temperature to the desired range. A secondary efficacy endpoint was a clinically meaningful hourly sweat output, defined as ≥150 mL/h. The primary safety endpoint was any procedure-related adverse events. RESULTS: We studied 6 normal subjects and 18 patients with congestion. Participants underwent 3 treatment sessions of up to 4 hours. Skin temperature increased to a median of 37.5 °C (interquartile range, 37.1-37.9 °C) with the median core temperature increasing by 0.2 °C (interquartile range, 0.1-0.3 °C). The median hourly weight loss during treatment was 215 g/h (interquartile range, 165-285; range, 100-344 g/h). In 80% of treatment procedures, the average sweat rate was ≥150 mL/h. There were no significant changes in hemodynamic variables or renal function and no procedure-related adverse events. CONCLUSIONS: Enhancing sweat rate was safe and resulted in a clinically meaningful fluid removal and weight loss. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04578353.

Hyponatremia and long-term mortality in survivors of acute ST-elevation myocardial infarction.

BACKGROUND: Hyponatremia, a marker of neurohormonal activation, is a common electrolyte disorder among patients with acute ST-elevation myocardial infarction. The long-term prognostic value of hyponatremia during the acute phase of infarction is not known. METHODS: We studied 978 patients with acute ST-elevation myocardial infarction and without a history of heart failure who survived the index event. During the hospital stay, sodium levels were obtained on admission and at 24, 48, and 72 hours. The median duration of follow-up after hospital discharge was 31 months (range, 9-61 months). RESULTS: Hyponatremia, defined as a mean serum sodium level less than 136 mEq/L, was present during admission in 108 patients (11.0%). In a multivariable Cox proportional hazards model adjusting for other potential clinical predictors of mortality and for left ventricular ejection fraction, hyponatremia during admission remained an independent predictor of postdischarge death (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.3-3.2; P = .002). Hyponatremia during admission was also independently associated with postdischarge readmission for heart failure (HR, 1.6; 95% CI, 1.1-2.6; P = .04). When serum sodium level was used as a continuous variable, the adjusted HR for death or heart failure was 1.12 for every 1-mEq/L decrease (95% CI, 1.07-1.18; P<.001). CONCLUSION: Hyponatremia in the early phase of ST-elevation myocardial infarction is a predictor of long-term mortality and admission for heart failure after hospital discharge, independent of other clinical predictors of adverse outcome and left ventricular ejection fraction.

Effect of obesity on the relationship between plasma C-reactive protein and coronary artery stenosis in patients with stable angina.

INTRODUCTION: The association between plasma C-reactive protein (CRP) and the extent of coronary artery disease (CAD) in patients with stable angina remains controversial. Obesity is strongly associated with elevated CRP levels, potentially confounding the relationship between CRP and CAD severity. METHODS AND RESULTS: We studied 830 subjects without CAD and 218 patients with CAD undergoing elective coronary angiography. Geometric means of CRP were computed in a two-way analysis of covariance model in which study participants were stratified into nine groups according to CAD status (no CAD, single-vessel disease or multivessel disease) and tertiles of BMI. There was a significant interaction between CAD and categories of BMI with regard to CRP level (P=0.002). In the lower tertile of BMI, patients with CAD had markedly higher CRP concentration compared to control subjects (1.16, 1.80 and 2.82 mg/L in subjects without CAD, patients with single-vessel disease and patients with multivessel disease, respectively; P=0.003). However, the relationship between CRP and CAD became weaker for patients in the second BMI tertile (P=0.15), whereas no significant relationship was observed for patients in the third BMI tertile (P=0.75). In patients undergoing coronary angioplasty (n=195), BMI was independently related to the magnitude of the angioplasty-induced CRP elevations (P=0.002). CONCLUSION: The level of obesity is essential to the interpretation of the relationship between CRP and severity of CAD. The production of inflammatory mediators with increasing levels of obesity becomes the dominant determinant of plasma CRP levels and masks the vascular contribution due to CAD.

Preprocedural C-reactive protein levels predict myocardial necrosis after successful coronary stenting in patients with stable angina.

BACKGROUND: Myocardial necrosis as assessed by cardiac troponin elevation occurs frequently after coronary stenting and is associated with adverse clinical outcome. Mechanical factors have been implicated in this complication and the role of systemic inflammation is not known. METHODS: We prospectively studied 208 patients with chronic stable angina who underwent elective coronary stenting. All patients had normal troponin levels before the procedure. Blood samples for high-sensitivity C-reactive protein (CRP) were obtained before the procedure and analyzed using a high-sensitivity kit. Cardiac troponin T (cTnT) was obtained 24 hours after the procedure. RESULTS: Postprocedural cTnT elevations were observed in 46 (22%) patients. There were 11 (16%), 14 (20%), and 21 (30%) patients with elevated postprocedural cTnT in the first, second, and third CRP tertile, respectively (P for trend = .045). In a multivariate logistic regression model, adjusting for all the significant univariate predictors and for statin therapy, CRP remained a significant independent predictor of postprocedural cTnT elevation with an odds ratio of 2.6 in patients in the third CRP tertile compared with patients in the first CRP tertile (95% CI 1.1-6.0, P = .02). Patients in the third CRP tertile also had higher cTnT elevations compared with patients in the first and second CRP tertile (P = .03). CONCLUSIONS: Elevated baseline CRP levels are associated with higher risk of postprocedural troponin elevations in patients with stable angina undergoing uncomplicated coronary stenting. These results underscore the role of systemic inflammation in the pathogenesis of periprocedural myocardial injury.

Inhospital and 1-year mortality of patients who develop worsening renal function following acute ST-elevation myocardial infarction.

BACKGROUND: Recent studies have emphasized the prognostic value of baseline creatinine or estimated creatinine clearance in the setting of acute coronary syndromes. However, the prevalence and prognostic significance of worsening renal function (WRF) in patients with acute ST-elevation myocardial infarction are unknown. METHODS: We studied 1038 patients presenting with acute ST-elevation infarction. WRF was defined as an increase of > or =0.5 mg/dL in creatinine level at any point during hospital stay. The relation between WRF and subsequent inhospital and 1-year mortality was analyzed by use of multivariate logistic regression and Cox proportional hazards models, respectively, controlling for covariates. RESULTS: WRF occurred in 98 (9.6%) patients during hospital stay. Baseline renal dysfunction (calculated glomerular filtration rate <60 mL/min) and WRF were strong independent predictors of inhospital mortality (adjusted odds ratios 2.8, 95% CI 1.3-5.9; and 11.4, 95% CI 6.6-19.5, respectively). In a Cox multivariate analysis, both baseline renal dysfunction (adjusted hazard ratio 2.8, 95% CI 1.6-4.9) and WRF (adjusted hazard ratio 7.2, 95% CI 4.9-10.4) remained independent predictors of 1-year mortality. WRF provided incremental prognostic value toward the prediction of 1-year mortality when added to clinical risk predictors and baseline renal function. The increased mortality associated with impaired baseline renal function was largely caused by events occurring in patients with WRF. CONCLUSION: WRF occurring during admission for ST-elevation myocardial infarction is a powerful and independent predictor of inhospital and 1-year mortality. Small elevations of serum creatinine may serve as a simple marker to identify patients at a very high risk.

Prognostic importance of hyponatremia in acute ST-elevation myocardial infarction.

PURPOSE: To determine the prevalence and prognostic implications of hyponatremia in the setting of acute ST-elevation myocardial infarction. METHODS: The study sample consisted of 1047 consecutive patients presenting with acute ST-elevation myocardial infarction. Plasma sodium concentrations were obtained on admission and at 24, 48, and 72 hours thereafter. Infarct size was determined by echocardiographic examination that was performed on day 2 or 3 of hospitalization. RESULTS: Hyponatremia, defined as a plasma sodium level <135 mmol/L (<135 mEq/L), was present on admission in 131 patients (12.5%) and developed during the first 72 hours of hospitalization in 208 patients (19.9%). Plasma sodium levels decreased to < or = 130 mmol/L in 45 patients (4.3%). In a multivariate logistic regression analysis, hyponatremia was independently associated with 30-day mortality. The risk of 30-day mortality associated with hyponatremia on admission (odds ratio [OR] = 2.0; 95% confidence interval [CI]: 1.0 to 3.9; P = 0.04) was similar to that of hyponatremia developing after admission (OR = 2.4; 95% CI: 1.5 to 4.2; P = 0.002). The risk of 30-day mortality increased with the severity of hyponatremia, with an odds ratio of 2.1 in patients with sodium levels between 130 and 134 mmol/L (95% CI: 1.2 to 3.5; P = 0.007) and 3.4 in those with levels <130 mmol/L (95% CI: 1.5 to 7.8; P = 0.002). CONCLUSION: Hyponatremia on admission or early development of hyponatremia in patients with acute ST-elevation myocardial infarction is an independent predictor of 30-day mortality, and prognosis worsens with the severity of hyponatremia. Further studies are required to determine if plasma sodium levels may serve as a simple marker to identify patients at high risk.

Percutaneous coronary interventions in diabetic patients: is complete revascularization important?

BACKGROUND: The long-term prognosis of diabetic patients with multivessel coronary artery disease (CAD) treated by surgical or percutaneous coronary revascularization is significantly worse as compared to non-diabetics. Lower rates of complete revascularization may be one factor that influences the poor long-term outcome in the diabetic population. Our study assessed the impact of complete revascularization on the long-term prognosis in diabetic patients with CAD treated by percutaneous coronary intervention (PCI). The study included 658 consecutive diabetic patients (mean age, 60.9+/-10.1 years) who underwent PCI. Multivessel disease was present in 352 patients (53.5%). Revascularization was complete in 94 (26.7%) and incomplete in 258 (73.3%) patients with multivessel disease. Reasons for incomplete revascularization included angioplasty of only the culprit lesion (43.4%); small vessel size (22.8%); moderate lesion, defined as diameter stenosis 50-69% (18.6%); chronic total occlusion of the non-intervened vessel (6.6%); and others (8.5%). Overall survival rate at 5 years was 87.4%. Patients who underwent complete revascularization had a 94.5% survival rate, compared to 83.0% for those with incomplete revascularization (p<0.001). Similarly, the rates of myocardial infarction-free survival were significantly higher in patients with complete versus incomplete revascularization (92.9% versus 79.9%, respectively). Incomplete revascularization was the most powerful independent predictor of mortality at follow-up (relative risk 95% confidence interval, 1.54-7.69; p=0.003). Our data suggest that complete myocardial revascularization may improve the long-term prognosis after PCI of diabetic patients with multivessel CAD.

Clopidogrel Therapy Discontinuation Following Drug Eluting Stent Implantation in Real World Practice in Israel.

BACKGROUND: Incidence and predictors of clopidogrel discontinuation after drug eluting stent (DES) implantation, in real world practice, are poorly known. METHODS: Prospective study included all patients who underwent implantation of at least one DES between February 2006 and January 2007. Predictors of clopidogrel discontinuation were assessed by a multivariable analysis. RESULTS: In 269 patients, mean period for clopidogrel therapy was 13.2 ± 7.2 month. Twenty eight patients (10.4%) discontinued clolopidogrel prematurely (< 3 months). Early clopidogrel discontinuation was a predictor of late stent thrombosis (P = 0.005) and urgent target vessel revascularization (P = 0.05). There was a trend for higher cardiac mortality among that group (P = 0.07). By 12 months, 173 patients (64.3%) have discontinued clopidogrel therapy. The most frequent circumstance to stop clopidogrel before 12 months was recommendation of family physician. Patients that were followed by cardiologist were more encouraged to longer clopidogrel therapy. In multivariable analysis being non Jew (OR 19.2, 95% CI 2.4 to 142, P = 0.005), not followed by cardiologist (OR 4.7, 95% CI 1 to 23.1, P = 0.05) and lack of information regarding the importance of clopidogrel maintenance at discharge from hospital (OR 10.8, 95% CI 2.7 to 42.9, P = 0.001) were independent predictors of early clopidogrel discontinuation. CONCLUSIONS: Clopidogrel discontinuation, in real world practice is not unusual and related to poor outcome. Education for general physicians, clear instructions about the importance of antiplatelet maintenance at discharge and follow up by an expert cardiologist are opportunities to improve adherence do antiplatelet therapy following DES implantation.

Incidence, predictors and outcome of drug-eluting stent thrombosis in real-world practice.

BACKGROUND: Traditionally, stent thrombosis (STH) has been regarded as a complication of percutaneous coronary interventions during the first 30 post-procedural days. However, delayed endothelialization associated with the implantation of drug-eluting stents (DES) may extend the risk of thrombosis beyond 30 days. Data are limited regarding the risks and the impact of this phenomenon outside clinical trials. OBJECTIVES: To evaluate the incidence, predictors and clinical outcomes of STH and premature discontinuation of thienopyridines after implantation of DES in real-world practice. METHODS: We prospectively collected data from consecutive unselected patients who underwent at least 1 DES implantation at our center from February 2006 until January 2007. The patients were followed by a phone interview or by collecting data from admission files over the course of 2 years after the implantation. Confirmed and suspected STH was defined as accepted in the medical literature. RESULTS: Three hundred fourteen patients were successfully treated with DES (436 lesions). At 20 ± 6.7 months' follow up (median 22 months), 14 patients (4.4%) had STH (incidence density 2.7 cases/100 patients-years). Five patients had early thrombosis (0-30 days), 5 patients had late STH (31-360 days from the procedure) and 4 patients had very late STH (> 360 days). Five of the 14 patients with STH died (case fatality rate, 36%). In multivariant logistic regression analysis, history of a non-cardiac thrombotic event was a risk factor for STH (p = 0.006, odds ratio [OR] 7.7, confidence interval [CI] 1.8-32.9). Clopidogrel therapy lasting less than 3 months was an independent predictor of late and very late STH (p = 0.001, OR 10.8, CI 2.7-42.9). Independent predictors of early discontinuation of thienopyridines (≤ 3 months) were Arab ethnic origin (p = 0.005, OR 19.2, CI 2.4-142), absence of cardiology follow up (p = 0.05, OR 4.7, CI 1-23.1) and absence of explanation about the clopidogrel importance at the time of hospital discharge (p = 0.001, OR 10.8, CI 2.7-42.9). CONCLUSIONS: The incidence of STH at 22- month follow up in real-world patients was substantially higher than the rate reported in previous clinical trials. Subsidizing the cost of thienopyridines, providing a clear explanation to the patient and encouraging cardiology follow up may prevent premature discontinuation of thienopyridines after implantation of DES and reduce the incidence of STH after DES implantation.