Nolwenn Merlet

Investigational drugs targeting cardiac fibrosis

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.

Validating a bimodal intravascular ultrasound (IVUS) and near-infrared fluorescence (NIRF) catheter for atherosclerotic plaque detection in rabbits.

Coronary artery disease is characterized by atherosclerotic plaque formation. Despite impressive advances in intravascular imaging modalities, in vivo molecular plaque characterization remains challenging, and different multimodality imaging systems have been proposed. We validated an engineered bimodal intravascular ultrasound imaging (IVUS) / near-infrared fluorescence (NIRF) imaging catheter in vivo using a balloon injury atherosclerosis rabbit model. Rabbit aortas and right iliac arteries were scanned in vivo after indocyanine green (ICG) injection, and compared to corresponding ex vivo fluorescence and white light images. Areas of ICG accumulation were colocalized with macroscopic atherosclerotic plaque formation. In vivo imaging was performed with the bimodal catheter integrating ICG-induced fluorescence signals into cross-sectional IVUS imaging. In vivo ICG accumulation corresponded to ex vivo fluorescence signal intensity and IVUS identified plaques.

Cardiac consequences of anti-inflammatory drugs in experimental models.

Although heart failure is predominantly caused by cardiovascular conditions such as hypertension, coronary heart disease and valvular heart disease, it can also be caused by adverse drug reactions. Several medications have been shown to have cardiotoxic effects. Among those therapeutic agents, anti-inflammatory drugs, including exogenous glucocorticoids, nonsteroidal anti-inflammatory drugs and biologics, which are used to treat a broad range of diseases that are associated with inflammatory processes, are widely prescribed in clinical practice. In this review, we discuss insights from experimental models on the beneficial and cardiotoxic effects of anti-inflammatory drugs.

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.

New Insights in Research About Acute Ischemic Myocardial Injury and Inflammation

Recognition that inflammation may contribute to the pathogenesis of various cardiac diseases has naturally led to the evaluation of the therapeutic potential of a range of anti-inflammatory approaches. Unfortunately, results in most settings have been disappointing. The majority of novel approaches fail despite promising preclinical data, partly attributable to off-target effects. The purpose of this review, focused on inflammation following acute myocardial ischemia, is to give a brief overview of the new insights regarding research on pro-inflammatory signaling cascades that could be targeted for cardioprotective therapeutic developments.

Adenylate Cyclase Type 9 (ADCY9) Inactivation Protects from Atherosclerosis Only in the Absence of Cholesteryl Ester Transfer Protein (CETP)

Background: Pharmacogenomic studies have shown that ADCY9 genotype determines the effects of the CETP (cholesteryl ester transfer protein) inhibitor dalcetrapib on cardiovascular events and atherosclerosis imaging. The underlying mechanisms responsible for the interactions between ADCY9 and CETP activity have not yet been determined. Methods: Adcy9-inactivated (Adcy9Gt/Gt) and wild-type (WT) mice, that were or not transgenic for the CETP gene (CETPtgAdcy9Gt/Gt and CETPtgAdcy9WT), were submitted to an atherogenic protocol (injection of an AAV8 [adeno-associated virus serotype 8] expressing a PCSK9 [proprotein convertase subtilisin/kexin type 9] gain-of-function variant and 0.75% cholesterol diet for 16 weeks). Atherosclerosis, vasorelaxation, telemetry, and adipose tissue magnetic resonance imaging were evaluated. Results: Adcy9Gt/Gt mice had a 65% reduction in aortic atherosclerosis compared to WT (P<0.01). CD68 (cluster of differentiation 68)-positive macrophage accumulation and proliferation in plaques were reduced in Adcy9Gt/Gt mice compared to WT animals (P<0.05 for both). Femoral artery endothelial-dependent vasorelaxation was improved in Adcy9Gt/Gt mice (versus WT, P<0.01). Selective pharmacological blockade showed that the nitric oxide, cyclooxygenase, and endothelial-dependent hyperpolarization pathways were all responsible for the improvement of vasodilatation in Adcy9Gt/Gt (P<0.01 for all). Aortic endothelium from Adcy9Gt/Gt mice allowed significantly less adhesion of splenocytes compared to WT (P<0.05). Adcy9Gt/Gt mice gained more weight than WT with the atherogenic diet; this was associated with an increase in whole body adipose tissue volume (P<0.01 for both). Feed efficiency was increased in Adcy9Gt/Gt compared to WT mice (P<0.01), which was accompanied by prolonged cardiac RR interval (P<0.05) and improved nocturnal heart rate variability (P=0.0572). Adcy9 inactivation–induced effects on atherosclerosis, endothelial function, weight gain, adipose tissue volume, and feed efficiency were lost in CETPtgAdcy9Gt/Gt mice (P>0.05 versus CETPtgAdcy9WT). Conclusions: Adcy9 inactivation protects against atherosclerosis, but only in the absence of CETP activity. This atheroprotection may be explained by decreased macrophage accumulation and proliferation in the arterial wall, and improved endothelial function and autonomic tone.