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Background: Ischemic mitral regurgitation (MR) is primarily caused by left ventricle deformation, but leaflet thickening with fibrotic changes are also observed in the valve. Increased levels of 5-hydroxytryptamine (5-HT; ie, serotonin) are described after myocardial infarction (MI); 5-HT can induce valve fibrosis through the 5-HT type 2B receptor (5-HT2BR)., Objectives: This study aims to test the hypothesis that post-MI treatment with cyproheptadine (5-HT2BR antagonist) can prevent ischemic MR by reducing the effect of serotonin on mitral biology., Methods: Thirty-six sheep were divided into 2 groups: inferior MI and inferior MI treated with cyproheptadine (0.5 mg/kg/d). Animals were followed for 90 days. Blood 5-HT, infarct size, left ventricular volume and function, MR fraction and mitral leaflet size were assessed. In a complementary in vitro study, valvular interstitial cells were exposed to pre-MI and post-MI serum collected from the experimental animals., Results: Increased 5-HT levels were observed after MI in nontreated animals, but not in the group treated with cyproheptadine. Infarct size was similar in both groups (11 ± 3 g vs 9 ± 5 g; P = 0.414). At 90 days, MR fraction was 16% ± 7% in the MI group vs 2% ± 6% in the cyproheptadine group (P = 0.0001). The increase in leaflet size following MI was larger in the cyproheptadine group (+40% ± 9% vs +22% ± 12%; P = 0.001). Mitral interstitial cells overexpressed extracellular matrix genes when treated with post-MI serum, but not when exposed to post-MI serum collected from treated animals., Conclusions: Cyproheptadine given after inferior MI reduces post-MI 5-HT levels, prevents valvular fibrotic remodeling, is associated with larger increase in mitral valve size and less MR., Competing Interests: Funding Support and Author Disclosures This work has been funded by the Canadian Institutes for Health Research (CIHR—grant #399323). Dr Clavel is supported by a New National Investigator from the Heart and Stroke Foundation of Canada and an Early Carrier Investigator Award from the CIHR. Dr Beaudoin is supported by the Fonds de Recherche du Québec-Santé (FRQS). The other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Aim of the Study: Aortic valve sclerosis is fairly common and is currently seen as a marker of systemic atherosclerosis. For unclear reasons only a minority of those sclerotic valves will evolve to become stenotic suggesting that atherogenic factors alone are insufficient to explain the development of valve stenosis. We had reported in a model of cholesterol fed rabbits that a combination of high cholesterol with vitamin D supplementation was necessary to induce valve stenosis and significant calcium deposition whereas high cholesterol alone only induced a sclerosis of the valve. In this study, we further evaluated the role of vitamin D treatment in the development of aortic valve disease (sclerosis or stenosis) in this rabbit model., Methods: Rabbits were divided in 4 groups followed for 12 weeks: 1) no treatment; 2) cholesterol-enriched diet, 3) cholesterol-enriched diet + vitamin D2 (VD; 50000IU, daily) 4) VD alone for 12 weeks. Echocardiographic assessment of the aortic valve was done at baseline, and every 4 weeks thereafter. Aortic valve area, maximal and mean transvalvular gradients were recorded and compared over time. Immunohistological study of the valves of AS rabbits was also realized for several classical atherosclerosis markers., Results: Vitamin D2 treated animal did not develop any stenosis of the valve despite increased echogenicity due to diffuse calcium deposits on the leaflets without any atherosclerotic lesions. Only the combination of high cholesterol with VD resulted in a decrease of aortic valve area. Immunohistological analysis of aortic valves from VD rabbits showed the presence of calcium deposits, T-cell infiltration in addition to positive labeling for alpha-smooth muscle cell actin. We did not observe macrophage infiltration in aortic valve leaflets of VD rabbits., Conclusion: Hypercholesterolemia or vitamin D supplements alone could not induce aortic valve stenosis in our animal model whereas the combination resulted in a decreased aortic valve area. These findings support the hypothesis that a combination of atherosclerotic and calcifying factors is necessary to induce aortic valve stenosis in this model.

The early events leading to the establishment of left ventricular hypertrophy associated to pressure overload (PO) are not well characterized. To explore these early events, aortic banding (AB) was performed in rats to induce left ventricle (LV) PO. Animals were sacrificed after 24, 48 h or 14 days. An echocardiogram was performed before the procedure and at sacrifice. LVs were preserved for the evaluation of fibrosis, angiotensin II (AT) receptors expression and stress-related MAP kinases (ERK 1/2, JNK and p38) pathways. We observed that concentric LV hypertrophy was established after only 14 days. Collagen I and fibronectin gene expressions were decreased the first 2 days after AB induction whereas AT receptors mRNA levels were sharply increased. ERK 1/2 and JNK activities in LV homogenates were decreased 24 h after AB but came back to normal after 14 days. p38 activity however was stable during the period studied. We also evaluated the presence of two phosphorylated transcription factors related to JNK signaling pathway (ATF-2 and c-Jun) in cardiomyocyte nuclei. The proportion of LV cell nuclei positive for these two activated transcription factors was significantly reduced in AB rats compared to sham. These results suggest that the early response of the LV to acute PO is to attenuate the expression of some pro-fibrotic and pro-hypertrophic signaling pathways and possibly AT signaling by decreasing ERK 1/2 and JNK relative activities.

Objectives: This study sought to examine the association between the metabolic syndrome (MS) and the progression of aortic stenosis (AS)., Background: It has been suggested that aortic valve sclerosis and its progression to AS are caused by an atherosclerotic process. Metabolic syndrome is associated with a higher risk of vascular atherosclerosis. Thus, we hypothesized that the atherogenic features of MS could negatively influence disease progression and prognosis in patients with AS., Methods: We retrospectively analyzed the data of 105 consecutive patients (age 69 +/- 12 years, 64 men) with at least moderate AS. Of these patients, 40 (38%) had MS identified according to the modified clinical criteria proposed by the National Cholesterol Education Program-Adult Treatment Panel III. The hemodynamic progression of AS was assessed by the measurement of the annualized decrease in valve area during the follow-up period of the study, which averaged 28 +/- 13 months. Event-free survival was defined as the absence of death or aortic valve replacement during follow-up., Results: The hemodynamic progression of the stenosis was twice as fast (-0.14 +/- 0.13 cm2/year vs. -0.08 +/- 0.08 cm2/year, p = 0.008) and the three-year event-free survival was markedly lower (44 +/- 8% vs. 69 +/- 6%, p = 0.002) among patients with MS. In multivariate analysis, MS was found to be a strong independent predictor of both stenosis progression (p = 0.006) and event-free survival (odds ratio 3.85, 95% CI 1.96 to 7.58, p < 0.001)., Conclusions: The present study is the first to report that MS is associated with a faster disease progression and worse outcome in patients with AS. Such findings open new avenues of research and provide a strong impetus for the elaboration of additional prospective studies focusing on this association.

Objectives: The purpose of this study was to compare aortic valve function and morphology in adult wild-type (WT) mice and in low-density lipoprotein receptor-deficient (LDLr-/-) mice fed or not fed a high-fat/high-carbohydrate (HF/HC) diet., Background: Observations suggest a link between degenerative aortic valve stenosis (AS) and atherosclerosis. Aortic valve stenosis has been successfully induced in animal models of extreme hypercholesterolemia, but these models are less relevant to humans. It is not known if a proatherogenic HF/HC diet without added cholesterol could have the same negative impacts., Methods: Forty C57BL/6J mice were divided into four groups: WT + normal diet, WT + HF/HC diet, LDLr-/- with a normal diet, and LDLr-/- with a HF/HC diet. Aortic valve function and histology were evaluated by echocardiography after four months., Results: Wild-type mice on a HF/HC diet became mildly hypercholesterolemic, obese, and hyperglycemic. As expected, LDLr-/- mice became severely hypercholesterolemic. Both WT and LDLr-/- mice on a HF/HC diet displayed smaller valve areas and higher transvalvular velocities (p < 0.01) after four months. Aortic valve leaflets were thicker and infiltrated with lipids and macrophages in both HF/HC groups., Conclusions: A HF/HC diet in mice results in significant aortic valve abnormalities. Putting WT mice on a HF/HC diet reproduced a combination of atherogenic factors (obesity, mild dyslipidemia, and hyperglycemia) more commonly encountered in humans than isolated severe hypercholesterolemia. Severe hypercholesterolemia was not a prerequisite in our model. This experimental model suggests that AS development is multifactorial and that hypercholesterolemia should not be the only target in this disease.

Objectives: We studied a known rabbit model of atherosclerosis to assess the effect of a hypercholesterolemic diet on aortic valve morphology and function. We also evaluated the effects of the combination of this diet with vitamin D supplements on the development of the disease and the occurrence of valve calcification., Background: Aortic valve stenosis (AVS) is the most common valvular heart disease. Recent observations have suggested a link between atherosclerosis and the development of AVS. However, until now, there has been no solid direct proof of this potential link., Methods: Rabbits were divided in three groups: 1) no treatment; 2) cholesterol-enriched diet (0.5% cholesterol); and 3) cholesterol-enriched diet plus vitamin D(2) (50,000 IU/day). Echocardiographic assessment of the aortic valve was done at baseline and after 12 weeks of treatment. The aortic valve area (AVA) and maximal and mean transvalvular gradients were recorded and compared over time., Results: Control animals displayed no abnormalities of the aortic valve. Despite important increases in blood total cholesterol levels, animals in group 2 did not develop any significant functional aortic valve abnormality over 12 weeks. However, eight of 10 of the animals in group 3 developed a significant decrease in AVA (p = 0.004) and significant increases in transvalvular gradients (p = 0.003)., Conclusions: This study supports a potential link between atherosclerosis and the development of AVS. The differences noted between hypercholesterolemic animals with or without vitamin D(2) supplementation imply a significant role of calcium in the development of AVS, meriting further attention.