Annik Fortier

Cellular senescence in endothelial cells from atherosclerotic patients is accelerated by oxidative stress associated with cardiovascular risk factors.

Risk factors for cardiovascular diseases (CVD) increase oxidative stress, and they are proposed to hasten endothelial cell (EC) damage and dysfunction. Our objective was to elucidate the impact of chronic exposure to risk factors for CVD on senescence of EC isolated and cultured from internal mammary arterial segments of patients with severe coronary artery disease. Senescence induced by serial passages resulted in progressive telomere shortening, and short initial telomeres predicted early appearance of senescence in culture. Neither time course of senescence nor telomere length was age-dependent, suggesting that biological age, rather than chronological age, determined the dynamics. Senescence appeared earlier in patients with longer history of risk factor for CVD, and multivariate analysis suggested that hypertension hastened the onset of senescence. Risk factors for CVD override the effects of chronological aging likely by generating stress-dependent damage: senescent EC exhibited oxidative stress (increase in lipid peroxydation and caveolin-1 gene expression) and cell damage markers (loss of eNOS expression and increase in Cox2 mRNA, lower TRF1 protein level). Thus, cell senescence was triggered both by telomere-dependent and -independent pathways. In conclusion, chronic exposure to risk factors for CVD accelerated the development of endothelial senescence that could contribute to the pathogenesis of CVD.

Usefulness of self-reported leisure-time physical activity to predict long-term survival in patients with coronary heart disease.

Self-reported leisure-time physical activity level correlates well with both cardiovascular (CV) and non-CV mortality in subjects without coronary heart disease (CHD). The impact of leisure-time physical activity on long-term outcomes has not been well studied in patients with preexisting CHD, who are often physically limited because of symptoms, medications, and co-morbid conditions. The aim was to determine the long-term prognostic value of self-reported leisure-time physical activity in a large CHD cohort. Leisure-time physical activity was evaluated using a self-administered questionnaire and categorized using a 4-level scale (sedentary, mild, moderate, and strenuous) in 14,021 of 24,958 subjects from the Coronary Artery Surgery Study Registry with suspected or proven CHD who underwent cardiac catheterization from 1974 to 1979. Median long-term follow-up was 14.7 years (interquartile range 9.8 to 16.2). Clinical outcomes were evaluated according to physical activity level and adjusted for potential confounders. Long-term all-cause and CV mortality progressively increased from most to least active subjects, with sedentary patients showing a 1.6-fold increase in mortality for both these outcomes (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.34 to 1.97, p <0.0001 for all-cause mortality). Similar trends were noted for men and women and in adjusted models, although HRs were attenuated after adjusting for age, gender, smoking, hypertension, diabetes mellitus, total cholesterol, body mass index, and ejection fraction (adjusted HR 1.23, 95% CI 1.01 to 1.49, p = 0.03 for all-cause mortality; adjusted HR 1.25, 95% CI 0.99 to 1.57, p = 0.05 for CV mortality). In conclusion, leisure-time physical activity independently predicted long-term survival in men and women with chronic stable CHD.

Chronic treatment with N-acetyl-cystein delays cellular senescence in endothelial cells isolated from a subgroup of atherosclerotic patients

Endothelial senescence may contribute to the pathogenesis of age-related vascular disorders. Furthermore, chronic exposure to risk factors for cardiovascular disease (CVD) accelerates the effects of chronological aging by generating stress-dependent damages, including oxidative stress, therefore promoting stress-induced premature senescence. Our objective was to determine whether a chronic treatment with an antioxidant (N-acetyl-cystein, NAC) could delay senescence of endothelial cells (EC) isolated and cultured from arterial segments of patients with severe coronary artery disease. If EC were considered as one population (n=26), chronic NAC treatment slightly shortened telomere attrition rate associated with senescence but did not significantly delay the onset of endothelial senescence. However, in a subgroup of NAC-treated EC (n=15) cellular senescence was significantly delayed, NAC decreased lipid peroxidation (HNE), activated the catalytic subunit of telomerase (hTERT) and inhibited telomere attrition. In contrast, in another subgroup of EC (n=11) characterized by initial short telomeres, no effect of NAC on HNE and high levels of DNA damages, the antioxidant was not beneficial on senescence, suggesting an irreversible stress-dependent damage. In conclusion, chronic exposure to NAC can delay senescence of diseased EC via hTERT activation and transient telomere stabilization, unless oxidative stress-associated cell damage has become irreversible.

In vivo myocardial distribution of multipotent progenitor cells following intracoronary delivery in a swine model of myocardial infarction

AIMS There are few data comparing the fate of multipotent progenitor cells (MPCs) used in cardiac cell therapy after myocardial infarction (MI). To document in vivo distribution of MPCs delivered by intracoronary (IC) injection. METHODS AND RESULTS Using an anterior MI swine model, near-infrared (NIR) fluorescence was used for in vivo tracking of labelled MPCs [mesenchymal stromal (MSCs), bone marrow mononuclear (BMMNCs), and peripheral blood mononuclear (PBMNCs)] cells early after IC injection. Signal intensity ratios (SIRs) of injected over non-injected (reference) zones were used to report NIR fluorescence emission. Following IC injection, significant differences in mean SIR were documented when MSCs were compared with BMMNCs [1.28 +/- 0.10 vs. 0.77 +/- 0.11, P < 0.001; 95% CI (0.219, 0.805), respectively] or PBMNCs [1.28 +/- 0.10 vs. 0.80 +/- 0.14, P = 0.005; 95% CI (0.148, 0.813), respectively]. Differences were maintained during the 60 min tracking period, with only the MSC-injected groups continuously emitting NIR fluorescence (SIR>1). This is correlated with greater cell retention for MSCs relative to mononuclear cells. However, there was evidence of MSC-related vessel plugging in some swine. CONCLUSION Our in vivo NIR fluorescence findings suggest that MPC distribution and retention immediately after intracoronary delivery vary depending on cell population and could potentially impact the clinical efficacy of cardiac cell therapy.

Pexelizumab fails to inhibit assembly of the terminal complement complex in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Insight from a substudy of the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial.

BACKGROUND Reasons for pexelizumab lack of benefit in ST-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention remain unclear. In a substudy of the APEX-AMI trial, we explored the hypothesis that early complement activation preceding drug administration explained the failure. METHODS A panel of terminal complement complex proteins and fragments and biomarkers of inflammation, apoptosis, and high-risk features were assessed in serum obtained before and 24 hours after administration of placebo or pexelizumab and primary percutaneous coronary intervention (n = 356) and in human umbilical vein endothelial cell cultures coincubated with serum (n = 45). RESULTS In the placebo group, C5a and sC5b-9 levels increased by 37% (7.9-14.2 ηg/mL, P = .007) and 96% (442-845 ηg/mL, P < .0001), respectively, during the first 24 hours. Pexelizumab prevented the increase in C5a (P = .01 vs placebo), but not that of sC5b-9 (502-1,157 ηg/mL, not significant vs placebo). Levels of C-reactive protein, interleukin (IL) 6, IL-1ß, Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) or Chemokine C-C motif ligand 5 (CCL5), and N-terminal probrain natriuretic peptide increased significantly in both groups; those of IL-10, IL-12, IL-1ra, and Interferon gamma-induced protein 10 (IP-10) or C-X-C motif chemokine 10 (CXCL10) decreased. Pexelizumab halved the increase in IL-6 (+92% vs 156%, P = .01) without effects on other markers, including C-reactive protein and N-terminal probrain natriuretic peptide. In cell culture, pexelizumab inhibited C5a, sC5b-9, and membrane-bound C5b-9 by 92%, 75%, and 78%, respectively (all P < .0001), without influencing cytokine levels and cell apoptosis. CONCLUSIONS The blockage of both C5a and terminal complement in cell culture, but of C5a only in vivo with minimal effects on inflammation and risk biomarkers, supports the hypothesis that late administration of pexelizumab after the ischemia/reperfusion insult precluded adequate myocardial protection, resulting in a negative trial.

Heart Rate Recovery After Exercise and Long-term Prognosis in Patients With Coronary Artery Disease

BACKGROUND The long-term prognostic value of heart rate recovery (HRR) has been incompletely documented in patients with coronary artery disease (CAD). We sought to confirm the prognostic value of HRR in a large cohort with stable CAD. METHODS From the Coronary Artery Surgery Study registry, a database of 24,958 patients with CAD who underwent cardiac catheterization between 1974 and 1979, we identified 4097 patients with baseline exercise stress testing data. HRR was measured at 3 minutes post exercise during a passive recovery. Clinical outcomes were evaluated according to HRR in both threshold and continuous models. RESULTS Median long-term follow-up was 14.7 years (interquartile range, 9.8-16.2). HRR < 46 beats per minute (Bpm) most appropriately differentiated nonsurvivors from survivors (area under receiver operating characteristic curve = 0.613) and was associated with an increased risk of all-cause death (adjusted hazard ratio = 1.15; P = 0.011). Increasing HRR was associated with a lower risk of all-cause (adjusted hazard ratio = 0.94 per 10 Bpm; 95% confidence interval, 0.91-0.97; P = 0.0005) and cardiovascular (CV) mortality (adjusted hazard ratio = 0.94 per 10 Bpm; 95% confidence interval, 0.90-0.98; P = 0.003). CONCLUSIONS HRR at 3 minutes independently predicts long-term all-cause and CV mortality in patients with stable CAD. Measurement of HRR at 3 minutes during passive recovery can be used as a complementary tool to identify patients with a higher total and CV risk.

Risk Factors Involved in Central-to-Radial Arterial Pressure Gradient During Cardiac Surgery.

BACKGROUND:A central-to-radial arterial pressure gradient may occur after cardiopulmonary bypass (CPB), which, in some patients, may last for a prolonged time after CPB. Whenever there is a pressure gradient, the radial artery pressure measure may underestimate a more centrally measured systemic pressure, which may result in a misguided therapeutic strategy. It is clinically important to identify the risk factors that may predict the appearance of a central-to-radial pressure gradient, because more central sites of measurements might then be considered to monitor systemic arterial pressure in high-risk patients. The objective of this study was to assess preoperative and intraoperative risk factors for central-to-radial pressure gradient. METHODS:Seventy-three patients undergoing cardiac surgery using CPB were included in this prospective observational study. A significant central-to-radial arterial pressure gradient was defined as a difference of 25 mm Hg in systolic pressure or 10 mm Hg in mean arterial pressure for a minimum of 5 minutes. Preoperative data included demographics, presence of comorbidities, and medications. Intraoperative data included type of surgery, CPB and aortic clamping time, use of inotropic drugs, and vasodilators or vasopressors agents. The diameter of the radial and femoral artery was measured before the induction of anesthesia using B-mode ultrasonography. RESULTS:Thirty-three patients developed a central-to-radial arterial pressure gradient (45%). Patients with a significant pressure gradient had a smaller weight (71.0 ± 16.9 vs 79.3 ± 17.3 kg, P = 0.041), a smaller height (162.0 ± 9.6 vs 166.3 ± 8.6 cm, P = 0.047), a smaller radial artery diameter (0.24 ± 0.03 vs 0.29 ± 0.05 cm, P < 0.001), and were at a higher risk as determined by the Parsonnet score (30.3 ± 24.9 vs 17.0 ± 10.9, P = 0.007). In addition, a longer aortic clamping time (85.8 ± 51.0 vs 64.2 ± 29.3 minutes, P = 0.036), mitral and complex surgery (P = 0.007 and P = 0.017, respectively), and administration of vasopressin (P = 0.039) were identified as potential independent predictors of a central-to-radial pressure gradient. By using multivariate logistic regression analysis, the following independent risk factors were identified: Parsonnet score (odds ratio [OR], 1.076; 95% confidence interval [CI], 1.027–1.127, P = 0.002), aortic clamping time >90 minutes (OR, 8.521; 95% CI, 1.917–37.870, P = 0.005), and patient height (OR, 0.933, 95% CI, 0.876–0.993, P = 0.029). The relative risk (RR) estimates remained statistically significant for the Parsonnet score and the aortic clamping time ≥90 minutes (RR, 1.010; 95% CI, 1.003–1.018, P = 0.009 and RR, 2.253; 95% CI, 1.475–3.443, P < 0.001 respectively) while showing a trend for patient height (RR, 0.974; 95% CI, 0.948–1.001, P = 0.058). CONCLUSIONS:Central-to-radial gradients are common in cardiac surgery. The threshold for using a central site for blood pressure monitoring should be low in small, high-risk patients undergoing longer surgical interventions to avoid inappropriate administration of vasopressors and/or inotropic agents.

Acute renal failure following lung transplantation: risk factors, mortality, and long-term consequences

OBJECTIVE Acute renal failure (ARF) frequently complicates lung transplantation. This study determined the prevalence, predictive factors, and consequences of ARF on long-term renal function and survival. METHODS One hundred and seventy-four lung transplantation recipients were divided into two groups based on the presence or absence of ARF defined as a 50% decrease in creatinine clearance from baseline (group I: 67 patients with ARF; group II: 107 patients without ARF). Multivariate analysis compared pre-operative, operative, and post-operative risk factors to assess predictive factors. Renal function over time was assessed by two-way repeated measures analysis of variance (ANOVA). RESULTS ARF developed in 67 (39%) of patients. Multivariate analysis identified aprotinin (OR 2.20 (1.11; 4.36), p=0.02) and double lung transplantation (OR 2.61 (1.32; 5.15), p=0.006) as risk factors for post-operative renal failure. At 5 years following transplant, creatinine clearance was similar between the two groups (group I CrCl: 73 ml s(-1); group II CrCl: 53 ml s(-1); p=0.54). Survival at 5 years was the same in the two groups. Multivariate analysis associated age at the time of transplantation (HR 1.030 (1.004; 1.057), p=0.02) and intensive care unit (ICU) length of stay (HR 1.029 (1.008; 1.051), p=0.007) with decreased survival. CONCLUSIONS The use of aprotinin and double lung transplantation are associated with ARF following lung transplantation. Age at the time of transplantation and a longer intensive care stay predict decreased survival. ARF after lung transplantation is not predictive of late renal dysfunction or decreased long-term survival.

Circulating levels of linoleic acid and HDL-cholesterol are major determinants of 4-hydroxynonenal protein adducts in patients with heart failure☆

Objective Measurements of oxidative stress biomarkers in patients with heart failure (HF) have yielded controversial results. This study aimed at testing the hypothesis that circulating levels of the lipid peroxidation product 4-hydroxynonenal bound to thiol proteins (4HNE-P) are strongly associated with those of its potential precursors, namely n-6 polyunsaturated fatty acids (PUFA). Methods and results Circulating levels of 4HNE-P were evaluated by gas chromatography-mass spectrometry in 71 control subjects and 61 ambulatory symptomatic HF patients along with various other clinically- and biochemically-relevant parameters, including other oxidative stress markers, and total levels of fatty acids from all classes, which reflect both free and bound to cholesterol, phospholipids and triglycerides. All HF patients had severe systolic functional impairment despite receiving optimal evidence-based therapies. Compared to controls, HF patients displayed markedly lower circulating levels of HDL- and LDL-cholesterol, which are major PUFA carriers, as well as of PUFA of the n-6 series, specifically linoleic acid (LA; P=0.001). Circulating 4HNE-P in HF patients was similar to controls, albeit multiple regression analysis revealed that LA was the only factor that was significantly associated with circulating 4HNE-P in the entire population (R2=0.086; P=0.02). In HF patients only, 4HNE-P was even more strongly associated with LA (P=0.003) and HDL-cholesterol (p<0.0002). Our results demonstrate that 4HNE-P levels, expressed relative to HDL-cholesterol, increase as HDL-cholesterol plasma levels decrease in the HF group only. Conclusion Results from this study emphasize the importance of considering changes in lipids and lipoproteins in the interpretation of measurements of lipid peroxidation products. Further studies appear warranted to explore the possibility that HDL-cholesterol particles may be a carrier of 4HNE adducts.

Is Patient-Prosthesis Mismatch a Perioperative Predictor of Long-Term Mortality After Aortic Valve Replacement?

OBJECTIVES To determine the perioperative predictors of long-term mortality after aortic valve replacement (AVR). The authors hypothesized that perioperative variables are more important predictors of mortality than patient-prosthesis mismatch (PPM). DESIGN A retrospective study of prospectively collected data. SETTING A tertiary care university hospital. PARTICIPANTS One-hundred-ninety-nine adult patients who underwent AVR. INTERVENTIONS After Research and Ethics Committee approval, the authors studied consecutive adult patients that underwent AVR in 1999 from the time of procedure to 5 years later. Demographic data, hemodynamic profile obtained after the induction of anesthesia, and perioperative data were analyzed. Primary endpoint was 5-year survival. MEASUREMENTS AND MAIN RESULTS Actuarial survival rate was 95.98%, 91.46%, and 81.91% at 30 days, 1 year, and 5 years, respectively. On univariate analysis, patients who died were significantly older (p<0.0001), had pulmonary hypertension (PHT), longer cardiopulmonary bypass (CPB) (p = 0.0001) and cross-clamping duration (p = 0.003), more frequent return to CPB (p = 0.036), or the use of an intra-aortic balloon pump to wean from CPB (p = 0.015). PPM was not related to 5-year mortality (p = 0.0649). Using Cox survival analysis, the only independent risk factors related to 5-year mortality after AVR were PHT using the mean arterial pressure-to-mean pulmonary artery pressure ratio (HR: 1.39, 95% CI 1.01-1.92, p = 0.0413) and the presence of complex separation from CPB (HR: 2.66, 95% CI 1.08-6.50, p = 0.0324). CONCLUSIONS In patients undergoing AVR, 5-year survival was mostly related to the severity of PHT and intraoperative factors, mainly complexity of weaning from CPB.