In Vivo Near-Infrared Fluorescence Imaging of Atherosclerosis Using Local Delivery of Novel Targeted Molecular Probes.

This study aimed to evaluate the feasibility and accuracy of a technique for atherosclerosis imaging using local delivery of relatively small quantities (0.04-0.4 mg/kg) of labeled-specific imaging tracers targeting ICAM-1 and unpolymerized type I collagen or negative controls in 13 rabbits with atheroma induced by balloon injury in the abdominal aorta and a 12-week high-cholesterol diet. Immediately after local infusion, in vivo intravascular ultrasonography (IVUS)-NIRF imaging was performed at different time-points over a 40-minute period. The in vivo peak NIRF signal was significantly higher in the molecular tracer-injected rabbits than in the control-injected animals (P < 0.05). Ex vivo peak NIRF signal was significantly higher in the ICAM-1 probe-injected rabbits than in controls (P = 0.04), but not in the collagen probe-injected group (P = 0.29). NIRF signal discrimination following dual-probe delivery was also shown to be feasible in a single animal and thus offers the possibility of combining several distinct biological imaging agents in future studies. This innovative imaging strategy using in vivo local delivery of low concentrations of labeled molecular tracers followed by IVUS-NIRF catheter-based imaging holds potential for detection of vulnerable human coronary artery plaques.

Impact of summer season on pre-hospital time delays in women and men undergoing primary percutaneous coronary intervention.

BACKGROUND: Pre-hospital delays have been associated with poor outcomes in patients with acute ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). It is currently unknown how environmental variables affect treatment delays in these patients. METHODS AND RESULTS: The association between environmental variables, time to treatment including transportation times and adverse in-hospital events was assessed in 1828 consecutive patients with STEMI undergoing primary PCI between 2010 and 2014 in the Montreal metropolitan area. Median[Q1;Q3] total ischemia time was significantly longer during summer season (April-September) as compared to winter season (October-March, 201[140;305] min vs 187[126;266] min, p = 0.022). This difference between seasons was due to a significant increase in median decision time to seek treatment for symptoms during summer (90[46;185] min vs 78[40;156], p = 0.004). The former peaked during July and August and was most pronounced in men. Hence, outside temperature and summer season were identified as strong predictors of prolonged decision time in patients with STEMI (p < 0.001 and p = 0.002, respectively). Transportation times slightly increased during winter season and snow fall, this difference, however, was not significant (p = 0.46). A significant increase in in-hospital adverse outcomes following primary PCI was observed during summer season as compared to winter season (7.2% vs 4.8%, p = 0.032). Accordingly, multivariate logistic regression models adjusted for baseline variables identified summer season as a strong predictor of periprocedural adverse events (OR 1.83, 95% CI 1.2-3.11, p = 0.037). CONCLUSION: Contrary to our initial hypothesis, pre-hospital delays in patients with STEMI are considerably longer and associated with adverse in-hospital outcomes during summer season. Considering the consequences of global warming, it is imperative that educational efforts targeting patients' perception are implemented to counter treatment delays.

Weather and risk of ST-elevation myocardial infarction revisited: Impact on young women.

BACKGROUND: During the last decade, the incidence and mortality rates of ST-elevation myocardial infarction (STEMI) has been steadily increasing in young women but not in men. Environmental variables that contribute to cardiovascular events in women remain ill-defined. METHODS AND RESULTS: A total of 2199 consecutive patients presenting with acute ST-elevation myocardial infarction (STEMI, 25.8% women, mean age 62.6±12.4 years) were admitted at the Montreal Heart Institute between June 2010 and December 2014. Snow fall exceeding 2cm/day was identified as a positive predictor for STEMI admission rates in the overall population (RR 1.28, 95% CI 1.07-1.48, p = 0.005), with a significant effect being seen in men (RR 1.30, 95% CI 1.06-1.53, p = 0.01) but not in women (p = NS). An age-specific analysis revealed a significant increase in hospital admission rates for STEMI in younger women ≤55 years, (n = 104) during days with higher outside temperature (p = 0.004 vs men ≤55 years) and longer daylight hours (p = 0.0009 vs men ≤55 years). Accordingly, summer season, increased outside temperature and sunshine hours were identified as strong positive predictors for STEMI occurrence in women ≤55 years (RR 1.66, 95% CI 1.1-2.5, p = 0.012, RR 1.70, 95% CI 1.2-2.5, p = 0.007, and RR 1.67, 95% CI 1.2-2.5, p = 0.011, respectively), while an opposite trend was observed in men ≤55 years (RR for outside temperature 0.8, 95% CI 0.73-0.95, p = 0.01). CONCLUSION: The impact of environmental variables on STEMI is age- and sex-dependent. Higher temperature may play an important role in triggering such acute events in young women.

Hockey Games and the Incidence of ST-Elevation Myocardial Infarction.

BACKGROUND: The association between diagnosed acute ST-elevation myocardial infarction (STEMI) and hockey games in the Canadian population is unknown. METHODS: We retrospectively analyzed the association between hockey games of the National Hockey League Montreal Canadiens and daily hospital admissions for acute STEMI at the Montreal Heart Institute, Canada. RESULTS: Between June 2010 and December 2014, a total of 2199 patients (25.9% women; mean age, 62.6 ± 12.4 years) were admitted for acute STEMI. An increase in STEMI admissions was observed the day after a hockey game of the Montreal Canadiens in the overall population (from 1.3 ± 1.2 to 1.5 ± 1.3), however, this difference was not significant (P = 0.1). The number of STEMI admissions increased significantly from 0.9 ± 1.0 to 1.2 ± 1.0 per day in men (P = 0.04), but not in women (P = 0.7). The association between ice hockey matches and STEMI admission rates was strongest after a victory of the Montreal Canadiens. Accordingly, an increased risk for the occurrence of STEMI was observed in the overall population (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.0-1.3; P = 0.037) when the Montreal Canadiens won a match. This association was present in men (HR, 1.2; 95% CI, 1.03-1.4; P = 0.02) but not in women (P = 0.87), with a most pronounced effect seen in younger men (younger than 55 years; HR, 1.4; 95% CI, 1.1-1.8; P = 0.009). CONCLUSIONS: Although a weak association between hockey games and hospital admissions for STEMI was found in our overall population, the event of a hockey game significantly increased the risk for STEMI in younger men. Preventive measures targeting behavioural changes could positively affect this risk.

Inflammation and beyond: new directions and emerging drugs for treating atherosclerosis.

INTRODUCTION: Cardiovascular (CV) atherosclerotic disease remains the leading cause of morbidity and mortality worldwide, despite the advances in contemporary therapies. Inflammation is an important process in atherosclerosis, leading to plaque rupture and acute coronary syndrome. Although statin therapy has substantially reduced CV events in primary and secondary prevention, many treated patients will have recurrent adverse CV events despite the standard of care. Thus, drug development aiming to target inflammatory pathways seems a promising avenue for novel therapies in atherosclerosis. Areas covered: Statins have been extensively studied and are the most effective lipid-lowering drugs available for CV prevention. Novel anti-inflammatory drugs are being tested in Phase II and III trials, targeting pathways like interleukin-1, leukotrienes, TNF-α, P-selectin, CCL2-CCR2 and MAP Kinase. Expert opinion: Novel anti-inflammatory therapies seem promising additions to address the residual CV risk present despite the current standard of care, but large clinical trials have not yet shown beneficial effects on clinical events. PCSK9 inhibitors have been shown to substantially reduce LDL-C, however their long-term safety and effects on CV risk are currently being investigated. Pharmacogenomics holds great potential in future lipid trials, enabling the identification of patients who will respond with greater benefits and smaller risk to therapies and to decrease failure rates in drug development, as genotype-dependent effects of the CETP inhibitor dalcetrapib were shown in the dal-OUTCOMES and dal-PLAQUE-2 trials.

Validating Intravascular Imaging with Serial Optical Coherence Tomography and Confocal Fluorescence Microscopy.

Atherosclerotic cardiovascular diseases are characterized by the formation of a plaque in the arterial wall. Intravascular ultrasound (IVUS) provides high-resolution images allowing delineation of atherosclerotic plaques. When combined with near infrared fluorescence (NIRF), the plaque can also be studied at a molecular level with a large variety of biomarkers. In this work, we present a system enabling automated volumetric histology imaging of excised aortas that can spatially correlate results with combined IVUS/NIRF imaging of lipid-rich atheroma in cholesterol-fed rabbits. Pullbacks in the rabbit aortas were performed with a dual modality IVUS/NIRF catheter developed by our group. Ex vivo three-dimensional (3D) histology was performed combining optical coherence tomography (OCT) and confocal fluorescence microscopy, providing high-resolution anatomical and molecular information, respectively, to validate in vivo findings. The microscope was combined with a serial slicer allowing for the imaging of the whole vessel automatically. Colocalization of in vivo and ex vivo results is demonstrated. Slices can then be recovered to be tested in conventional histology.

Pharmacogenomic approaches to lipid-regulating trials.

PURPOSE OF REVIEW: Randomized clinical outcome trials are costly, long, and often yield neutral or modestly positive results, and these issues have impeded cardiovascular drug development in the past decade. Despite the significant reduction of cardiovascular morbidity and mortality with statins, substantial residual risk of major cardiovascular events remains. This could be because of the difficulty of demonstrating benefits of new drugs in addition to the current standard of care in unselected populations as well as the interindividual variability in drug response. Pharmacogenomics is a promising avenue for the development of novel or failed drugs and for the repurposing of other medications. RECENT FINDINGS: Several variants were identified in genes that were associated with the effects of statins on plasma lipids. Genomic studies of mutations in genes that encode drug targets have the potential to inform on the link between drug therapy acting on those targets and clinical outcomes. Recently, ADCY9 gene variants were shown to be significantly associated with responses to dalcetrapib in terms of clinical outcomes, atherosclerosis imaging, cholesterol efflux, and inflammation, which provided support for the conduct of a new prospective clinical trial in a genetically determined population. SUMMARY: Pharmacogenomics hold great potential in future lipid trials to decrease failure rates in drug development and to identify patients who will respond with greater benefits and smaller risk.