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Introduction: The Fontan procedure is the palliative procedure of choice for patients with single ventricle physiology. Pulmonary vascular disease (PVD) is an important contributor to Fontan circulatory failure., Areas Covered: We review the pathophysiology of PVD in patients with Fontan palliation and share our initial experience with optical coherence tomography (OCT) in supplementing standard hemodynamics in characterizing Fontan-associated PVD. In the absence of a sub-pulmonary ventricle, low pulmonary vascular resistance (PVR; ≤2 WU/m 2 ) is required to sustain optimal pulmonary blood flow. PVD is associated with adverse pulmonary artery (PA) remodeling resulting from the non-pulsatile low-shear low-flow circulation. Predisposing factors to PVD include impaired PA growth, endothelial dysfunction, hypercoagulable state, and increased ventricular end-diastolic pressure. OCT parameters that show promise in characterizing Fontan-associated PVD include the PA intima-to-media ratio and wall area ratio (i.e. difference between the whole-vessel area and the luminal area divided by the whole-vessel area)., Expert Opinion: OCT carries potential in characterizing PVD in patients with Fontan palliation. PA remodeling is marked by intimal hyperplasia, with medial regression. Further studies are required to determine the role of OCT in informing management decisions and assessing therapeutic responses.

Aim: Few genome-wide association studies (GWASs) have been conducted to identify predictors of drug concentrations. The authors therefore sought to discover the pharmacogenomic markers involved in metoprolol pharmacokinetics. Patients & methods: The authors performed a GWAS of a cross-sectional study of 993 patients from the Montreal Heart Institute Biobank taking metoprolol. Results: A total of 391 and 444 SNPs reached the significance threshold of 5 × 10 -8 for metoprolol and α-OH-metoprolol concentrations, respectively. All were located on chromosome 22 at or near the CYP2D6 gene, encoding CYP450 2D6, metoprolol's main metabolizing enzyme. Conclusion: The results reinforce previous findings of the importance of the CYP2D6 locus for metoprolol concentrations and confirm that large biobanks can be used to identify genetic determinants of drug pharmacokinetics at a GWAS significance level.

Introduction : Elevated triglyceride (TG) level is a prevalent condition in the general population and in patients with cardiovascular (CV) risk even under statin therapy. Severe hypertriglyceridemia (HTG) puts patients at risk for acute pancreatitis. Several TG-lowering drugs failed in clinical trials, but subgroup analyses suggest that high-risk patients, such as those with atherogenic dyslipidemia or diabetes, benefit from TG lowering. Areas covered : We review advances for TG-lowering drugs in clinical development. These include selective PPARα modulators, omega-3 fatty acid formulations that have been approved for severe HTG, and inhibitors of apolipoprotein C-III, angiopoietin-like-3 or microsomal transfer protein. Lessons learned from the success of the phase 3 trial REDUCE-IT with high-dose icosapent ethyl are also reviewed. Expert opinion : We believe that TG-lowering therapies are coming of age as they will allow to treat patients with high CV risk and moderate HTG, including T2D subjects, as well as patients with severe HTG or even homozygous familial hypercholesterolemia, all of which being 'optimally' treated with a statin. More studies on the impact of therapy on quality of life in patients with severe HTG should be conducted with the help of patient registries.

Aim: To evaluate the impact of AGTR1 A1166C (rs5186) on the response to candesartan in patients with heart failure., Materials & Methods: Prospective, multicentre, open-label study. We studied 299 symptomatic patients with heart failure presenting a left ventricular ejection fraction ≤40%., Results: Reductions in the primary end points of natriuretic peptides were not significantly associated with AGTR1 A1166C. Nevertheless, carrying the 1166C allele was associated with a greater compensatory increase in renin activity (p = 0.037) after 16 weeks of treatment with candesartan and a more modest effect on aldosterone concentrations (p = 0.022)., Conclusion: AGTR1 1166C carriers may experience a greater long-term compensatory renin-angiotensin-aldosterone system activation following treatment with candesartan. Whether these associations ultimately influence clinical outcomes requires investigation. Clinicaltrials.gov : NCT00400582.

Blood lipids are important modifiable risk factors for coronary heart disease and various drugs have been developed to target lipid fractions. Considerable efforts have been made to identify genetic variants that modulate responses to drugs in the hope of optimizing their use. Pharmacogenomics and new biotechnologies now allow for meaningful integration of human genetic findings and therapeutic development for increased efficiency and precision of lipid-lowering drugs. Polygenic predictors of disease risk are also changing how patient populations can be stratified, enabling targeted therapeutic interventions to patients more likely to derive the highest benefit, marking a shift from single variant to genomic approaches in pharmacogenomics.

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.

Background: Mitral regurgitation (MR) is a common valvular heart disorder requiring intervention once it becomes severe. Transcatheter mitral repair with the MitraClip device is a safe and effective therapy for selected patients denied surgery. The authors sought to evaluate the clinical outcomes and economic impact of this therapy compared to medical management in heart-failure patients with symptomatic mitral regurgitation., Methods and Results: The study was comprised of two phases; an observational study of patients with heart failure and mitral regurgitation treated with either medical therapy or the MitraClip, and an economic model. Results of the observational study were used to estimate parameters for the decision model, which estimated costs, and benefits in a hypothetical cohort of patients with heart failure and moderate-to-severe mitral regurgitation treated with either standard medical therapy or MitraClip. The cohort of patients treated with the MitraClip was propensity matched to a population of heart failure patients, and their outcomes compared. At a mean follow-up of 22 months, all-cause mortality was 21% in the MitraClip cohort and 42% in the medical management cohort (p = .007). The decision model demonstrated that MitraClip increased life expectancy from 1.87-3.60 years and quality-adjusted life years (QALY) from 1.13-2.76 years. The incremental cost was $52,500 Canadian dollars, corresponding to an incremental cost-effectiveness ratio (ICER) of $32,300.00 per QALY gained. Results were sensitive to the survival benefit., Conclusion: In heart failure patients with symptomatic moderate-severe mitral regurgitation, therapy with the MitraClip is associated with superior survival and is cost-effective compared to medical therapy.

Pharmacogenomics (PGx) tests have the potential of improving the effectiveness of expensive new drugs by predicting the likelihood, for a particular patient, to respond to a treatment. The objective of this study was to develop a pharmacoeconomic model to determine the characteristics and the cost-effectiveness of a hypothetical PGx test, which would identify patients who are most likely to respond to an expensive treatment for chronic heart failure. For this purpose, we chose the example of ivabradine. Our results suggest that the use of a PGx test that could select a subgroup of patients to be treated with an expensive drug has the potential to provide more efficient drug utilization.

Several studies have underlined the beneficial effects of a lower heart rate on mortality in patients with chronic heart failure and reduced ejection fraction. In clinical practice, achieving a heart rate ≤70 bpm with beta-blockers is not always possible. In this context, the more recent guidelines added ivabradine to the management of those patients if heart rate remains ≥70 bpm in sinus rhythm and symptoms persist despite treatment with an evidence-based or maximum tolerated dose of a beta-blocker, an angiotensin converting enzyme inhibitor or angiotensin-receptor blocker, and a mineralocorticoid receptor antagonist. Ivabradine is a well-tolerated, safe and effective treatment option with the objective to improve prognosis, left ventricular structure and function, exercise tolerance and quality of life. Accordingly, the following article will evaluate the benefits of a combination of the currently recommended pharmacological therapy in chronic heart failure with the selective heart rate reducing agent ivabradine.

Aim: To optimally address the interindividual variability observed in pharmacokinetic drug response, we have created a custom genotyping panel that interrogates most of the key genetic variations present in a set of 181 prioritized genes responsible for the absorption, distribution, metabolism and excretion (ADME) of many therapeutic agents. This consensus list of genes and variants was based on the ADME core and extended gene lists compiled by a group of pharmaceutical companies as having relevance. Although these pharmacokinetic genes and pathways are well known, tools that can interrogate a large number of these genes simultaneously within a single experiment are not currently available., Methods: Using novel design strategies, we have developed an optimized and validated ADME genotyping panel, encompassing approximately 3000 variants, that has broad applicability to any study or clinical trial that would benefit from the evaluation of an extensive list of ADME genes., Results & Conclusion: Over the course of three design iterations, overall assay conversion rates were improved from 83 to 97% resulting in a panel that fills in many of the gaps in coverage present on currently available commercial genotyping assays. The utility of the assay has been demonstrated by the screening of more than 1000 samples resulting in the discovery of novel pharmacogenomic associations. The assay, and the underlying methods, will continue to be a valuable tool for use in future pharmacogenomic studies.

Fibrosis is an accumulation of proteins including collagen in the extracellular space, which has previously been considered as irreversible damage in various cardiovascular diseases including heart failure and hypertension. The pathophysiology of fibrosis is currently better understood and can be evaluated by non-invasive methods. Here, the authors present briefly the impact and molecular mechanisms of fibrosis in the myocardium and the promising therapeutic candidates including anti-hypertensive therapies, heart-rate lowering drugs, anti-inflammatory agents, as well as other innovative approaches such as inhibitors of growth factors, miRNA or cell therapy. Surrogate end points allow for larger clinical trials than previously possible with endomyocardial biopsies, and magnetic resonance and molecular imaging should open new fields of research on cardiac fibrosis. Several pre-clinical findings are very promising, and some clinical data support the proofs of concept, mainly those with inhibitors of the renin-angiotensin system. These approaches open the field for regression of fibrosis and include the following: first, some of these drugs are widely used like renin-angiotensin system inhibitors; second, inflammation modulators; third, in near future entirely new approaches targeting the TGF-β pathways, or others like cell therapies or genetic interventions.

Introduction: Atherosclerosis remains one of the main causes of cardiovascular disease., Areas Covered: A brief overview of the work summarized by Berman et al. [Berman JP, Farkouh ME, Rosenson RS. Emerging anti-inflammatory drugs for atherosclerosis. Expert Opin Emerg Drugs 2013;18(2):193-205] on the development of anti-inflammatory drugs to tackle atherosclerosis is provided., Expert Opinion: Indeed, recent data from clinical trials on anti-inflammatory drugs in coronary artery disease highlight the potential of such therapies.

Biomarkers have proven to be critical tools in both cardiovascular clinical practice and clinical research. In clinical practice, biomarkers are used to identify patients at risk for disease, stratify disease severity, guide intervention decisions and monitor patient response to therapy. Biomarkers are also used extensively to improve the design of cardiovascular clinical trials, identify 'at-risk' populations, allow for preliminary screening for response, identify appropriate dose ranges, study subgroup differences and identify early safety concerns. The purpose of this paper is to describe current key cardiovascular biomarker initiatives and to outline some of the important considerations in applying these biomarkers in a clinical trial setting, utilizing the examples of HDL cholesterol, HDL-targeted therapies and imaging tools used to assess HDL-targeted therapies as a case study.

CETP is the target of CETP inhibitors such as anacetrapib and the modulator dalcetrapib. Both molecules have entered Phase III clinical trials, with the ultimate goal of reducing cardiovascular events by raising HDL cholesterol. At the 600-mg dose selected for the dal-OUTCOMES study, dalcetrapib is expected to inhibit CETP activity by approximately 30% and raise HDL-C by approximately 30% with limited effects on LDL cholesterol. Importantly, dalcetrapib does not raise blood pressure or aldosterone levels, two effects previously associated with the CETP inhibitor torcetrapib. Dalcetrapib has been well tolerated at the 600-mg dose. In the dal-PLAQUE atherosclerosis imaging study, dalcetrapib reduced the enlargement of total vessel area over time. In May 2012, following the results of the second interim analysis of dal-OUTCOMES, the Data and Safety Monitoring Board recommended stopping the study owing to a lack of clinically significant benefit, which was followed by Roche's (Basel, Switzerland) decision to terminate the study and the dalcetrapib program (dal-HEART). Contrary to anacetrapib, a potent CETP inhibitor that markedly increases HDL cholesterol and significantly reduces LDL cholesterol, dalcetrapib has allowed us to test the hypothesis that an isolated, moderate elevation in HDL cholesterol prevents cardiovascular events.

Aim: The goal of this study was to evaluate the performance of four warfarin pharmacogenetic algorithms in a real clinical setting, namely the algorithms of Gage et al., Michaud et al., Wadelius et al. and the International Warfarin Pharmacogenetics Consortium algorithm., Patients & Methods: Data was obtained retrospectively for 605 patients who had initiated warfarin therapy at the Montreal Heart Institute. Warfarin dosing and International Normalized Ratio history were obtained from hospital charts and CYP2C9 and VKORC1 polymorphisms were genotyped., Results: The four algorithms produced similar accuracy with mean absolute error ranging from 1.36-1.52 mg/day and adjusted R(2) from 40-44%. Gage's algorithm and Wadelius' algorithm predicted the largest proportion of patients within ± 20% of their observed stable warfarin dose. For patients requiring low doses, Gage's algorithm provided the highest proportion of patients within ideal dose range (36.3%), while Wadelius' algorithm performed the best for patients requiring high doses (37.3% of patients within ideal dose range)., Conclusion: Our study demonstrates the value of published pharmacogenetic dosing algorithms for the prediction of warfarin doses, in particular for patients with low or high therapeutic dose requirements.

Atherosclerosis imaging plays a significant role in an understanding of the natural history of vascular disease and is increasingly used to assess the efficacy of novel therapeutics. Furthermore, the concepts of 'vulnerable plaque' and, more recently, of 'vulnerable patient' have driven cardiovascular imaging technologies to develop methods for expanded qualitative and quantitative analyses. Indeed, developmental efforts are underway to better demonstrate thin fibrous cap and large necrotic cores, and to determine the correlation between these findings and subsequent cardiovascular events. In this article, we consider a wide variety of cardiovascular imaging techniques that are used as biomarkers of atherosclerosis. These technologies include traditional imaging such as angiography, as well as advanced imaging techniques using both invasive and noninvasive approaches.

The Génome Québec and Montreal Heart Institute Pharmacogenomics Centre (Montreal, Canada), created in 2006, is a translational pharmacogenomics platform whose main objectives are to conduct pharmacogenomics research, provide pharmacogenomics services to the academic, biotechnology and pharmaceutical sectors, and integrate pharmacogenomics solutions into the healthcare system. The Centre has brought together a multidisciplinary team of researchers with expertise in genomics, bioinformatics and clinical trial research. All the Centre's clinical research studies are supported by the Centre's unique Good Laboratory Practice facility framework, which has the ability to perform pharmaceutical clinical trials and deliver clinical diagnostics under the highest standards. The Centre has successfully leveraged its experience and expertise in technology development and pharmacogenomics clinical trial work to attract funding and collaborative partnerships in both the public and private sectors.

Objective: Recent data suggested a relationship between carotid artery intima/media thickness and airway hyperresponsiveness (AHR). Our objective was to assess the potential relationship between AHR and coronary atherosclerosis plaque volume as assessed by 3-dimensional intravascular ultrasound (IVUS)., Methods: Thirty-six subjects had a spirometry and methacholine challenge, skin prick tests, blood sampling and induced sputum analysis., Results: We found five (13.9%) patients who presented AHR to methacholine. There was no significant difference between patients with and without AHR, in plaque volume (221 +/- 45 mm3 vs. 189 +/- 13 mm3, P = 0.4), lumen volume (187 +/- 11 mm3 vs. 221 +/- 11 mm3, P = 0.2), or in total vessel volume (377 +/- 20 mm3 vs. 415 +/- 20 mm3, P = 0.5), respectively. No relationship was found between AHR, cell counts and coronary atherosclerotic plaque, lumen or total vessel volumes. There were significantly more eosinophils (1.69 +/- 1.75% vs. 0.21 +/- 0.31%, P = 0.0007) and lymphocyte counts (3.75 +/- 1.59% vs. 2.25 +/- 1.12%, P = 0.03) in patients with AHR compared to patients without., Conclusion: In patients with stable coronary artery disease, the incidence of AHR was low and there was no relationship between AHR or airway inflammation and coronary atherosclerosis.

Objective: Accumulating evidence supports a role of 4-hydroxynonenal (4HNE) in oxidative-stress related diseases, but its specific contribution to disease development remains to be clarified. Further to our finding of high circulating 4HNE-protein thioether adducts (4HNE-P) in spontaneously hypertensive rats (SHRs), we aimed at correlating 4HNE-P with cardiac function and testing the impact of antioxidant therapy., Materials and Methods: The lipoperoxidation inhibitor probucol (10 mg/kg/day) or vehicle (corn oil) were administered daily (i.p.) for 4 weeks in 18-week-old SHRs (9 rats/group). Cardiac functions were assessed by echocardiography and 4HNE-P by gas chromatography/mass spectrometry., Results: Diastolic dysfunction worsened in SHRs receiving vehicle as reflected by changes (P < 0.05) in indexes of left ventricular relaxation (increased isovolumic relaxation time) and compliance (increased E-wave deceleration rate; EDR). Higher circulating 4HNE-P correlated with diastolic dysfunction (EDR: R(2) = 0.518; P < 0.001) and heart rate (R(2) = 0.225; P < 0.05). Probucol prevented the deterioration of diastolic function, while lowering the mean and median of circulating 4HNE-P by 21% and 35%, respectively., Conclusion: Collectively, these results support a role for 4HNE in the pathophysiological events linked to disease progression in SHRs.

More than 1 million percutaneous coronary interventions (PCIs) are performed yearly worldwide. Restenosis is the recurrent narrowing that can occur within 6 months following an initially successful PCI. Although drug-eluting stents have accomplished remarkable success, restenosis has not been eliminated and optimisation of both the polymers and drugs associated with them is desirable. This article reviews the presently available and potential preventive approaches against restenosis, including the sirolimus and paclitaxel drug-eluting stents.

AGI-1067, the monosuccinic acid ester of probucol, is a phenolic antioxidant member of a novel class of agents termed vascular protectants. It has strong antioxidant properties, equipotent to those of probucol, and anti-inflammatory properties. It inhibits gene expression of vascular cell adhesion molecule-1 and monocyte chemotactic protein-1 and has been effective at preventing atherosclerosis in all tested animal models. It also improved luminal dimensions of reference segments in the percutaneous coronary intervention (PCI) vessels in the CART-1 clinical trial, which suggests a direct anti-atherosclerosis effect. Two important trials that test the antioxidant/anti-inflammatory hypothesis are ongoing with AGI-1067: the Canadian Atherosclerosis and Restenosis Trial, which assesses its value for the reduction of both atherosclerosis progression in non-PCI vessels and post-PCI restenosis, and the Aggressive Reduction of Inflammation Stops Events trial, which is evaluating the effects of AGI-1067 on hard cardiovascular outcomes.