Effects of Cyproheptadine on Mitral Valve Remodeling and Regurgitation After Myocardial Infarction.

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.

Progression of aortic stenosis after an acute myocardial infarction.

BACKGROUND: Myocardial infarction (MI) has been shown to induce fibrotic remodelling of the mitral and tricuspid valves. It is unknown whether MI also induces pathological remodelling of the aortic valve and alters aortic stenosis (AS) progression. We thus compared AS progression after an acute MI and in patients with/without history of MI, and assessed post-MI pathobiological changes within the aortic valve leaflets in a sheep model. METHODS: Serial echocardiograms in human patients with AS were retrospectively analysed and compared between 3 groups: (1) acute MI at baseline (n=68), (2) prior history of MI (n=45) and (3) controls without MI (n=101). Annualised progression rates of AS severity were compared between these 3 groups. In addition, aortic valves were harvested from 15 sheep: (1) induced inferior MI (n=10) and (2) controls without MI (n=5), for biological and histological analyses. RESULTS: In humans, the acute MI, previous MI and control groups had comparable baseline AS severity. Indexed aortic valve area (AVAi) declined faster in the acute MI group compared with controls (-0.07±0.06 vs -0.04±0.04 cm2/m2/year; p=0.004). After adjustment, acute MI status was significantly associated with faster AVAi progression (mean difference: -0.013 (95% CI -0.023 to -0.003) cm2/m2/year, p=0.008). In the post-MI experimental animal model, aortic valve thickness and qualitative/quantitative expression of collagen were significantly increased compared with controls. CONCLUSIONS: The results of this study suggest that AS progression is accelerated following acute MI, which could be caused by increased collagen production and thickening of the aortic valve after the ischaemic event.

Pathophysiology, Diagnosis, and New Therapeutic Approaches for Ischemic Mitral Regurgitation.

Ischemic mitral regurgitation (MR) is a valvular complication frequently seen in patients with coronary artery disease and is associated with increased mortality and morbidity. Ischemic mitral regurgitation has a complex, heterogeneous, and still incompletely understood pathophysiology involving both the mitral valve and the left ventricle. The occurrence of valve regurgitation in patients with ischemic cardiomyopathy in return accelerates left ventricular remodelling and dysfunction, ultimately leading to irreversible heart failure. Diagnostic evaluation of ischemic MR is unique and different from the other causes of MR. The severity thresholds associated with outcomes are different from primary MR, and specific imaging characteristics are potentially useful to guide therapy. The use of imaging modalities such as 3-dimensional echocardiography and cardiac magnetic resonance imaging can refine the diagnostic evaluation and help in choosing the correct management. Although multiple treatments are available to improve ischemic MR, each therapeutic option is associated with limitations and incomplete success. Therapy has therefore to be individualised for each patient. Current options include optimal medical therapy, cardiac resynchronisation therapy, percutaneous or surgical revascularisation, surgical mitral repair or replacement, and new percutaneous interventions. This review aims to discuss the latest insights regarding the pathophysiology, diagnosis, and treatment of ischemic MR.

Attenuated Mitral Leaflet Enlargement Contributes to Functional Mitral Regurgitation After Myocardial Infarction.

BACKGROUND: Mitral leaflet enlargement has been identified as an adaptive mechanism to prevent mitral regurgitation in dilated left ventricles (LVs) caused by chronic aortic regurgitation (AR). This enlargement is deficient in patients with functional mitral regurgitation, which remains frequent in the population with ischemic cardiomyopathy. Maladaptive fibrotic changes have been identified in post-myocardial infarction (MI) mitral valves. It is unknown if these changes can interfere with valve growth and whether they are present in other valves. OBJECTIVES: This study sought to test the hypothesis that MI impairs leaflet growth, seen in AR, and induces fibrotic changes in mitral and tricuspid valves. METHODS: Sheep models of AR, AR + MI, and controls were followed for 90 days. Cardiac magnetic resonance, echocardiography, and computed tomography were performed at baseline and 90 days to assess LV volume, LV function, mitral regurgitation and mitral leaflet size. Histopathology and molecular analyses were performed in excised valves. RESULTS: Both experimental groups developed similar LV dilatation and dysfunction. At 90 days, mitral valve leaflet size was smaller in the AR + MI group (12.8 ± 1.3 cm2 vs. 15.1 ± 1.6 cm2, p = 0.03). Mitral regurgitant fraction was 4% ± 7% in the AR group versus 19% ± 10% in the AR + MI group (p = 0.02). AR + MI leaflets were thicker compared with AR and control valves. Increased expression of extracellular matrix remodeling genes was found in both the mitral and tricuspid leaflets in the AR + MI group. CONCLUSIONS: In these animal models of AR, the presence of MI was associated with impaired adaptive valve growth and more functional mitral regurgitation, despite similar LV size and function. More pronounced extracellular remodeling was observed in mitral and tricuspid leaflets, suggesting systemic valvular remodeling after MI.

Early Activation of Growth Pathways in Mitral Leaflets Exposed to Aortic Regurgitation: New Insights from an Animal Model.

BACKGROUND AND AIM OF THE STUDY: Mitral leaflet enlargement in patients with chronic aortic regurgitation (AR) has been identified as an adaptive mechanism potentially able to prevent functional mitral regurgitation (FMR) in response to left ventricular (LV) dilatation. The timing of valve enlargement is not known, and the related mechanisms are largely unexplored. METHODS: AR was induced in 58 rats, and another 54 were used as sham controls. Animals were euthanized at different time points after AR creation (48 h, one week, and three months), and AR severity, FMR and LV dilatation were assessed using echocardiography. Mitral valves were harvested to document the reactivation of embryonic growth pathways. RESULTS: AR animals had increased LV dimensions and mitral annulus size. No animal developed FMR. No change in leaflet length or thickness was seen at 48 h; however, anterior mitral leaflets were longer and thicker in AR animals at one week and three months. Molecular changes were present early (at 48 h and at one week), with positive staining for transforming growth factor-b1 (TGF-b1), Alpha-smooth muscle actin (α-SMA) and matrix metalloproteinase-2 (MMP-2), which suggested active matrix remodeling. Increased gene expression for collagen 1, TGF-ß1, α-SMA and MMP-2 was found in the mitral valve at 48 h and at one week, but after three months their expression had returned to normal. CONCLUSIONS: This model of AR induces active expansion and thickening of the mitral leaflets. Growth signals are expressed acutely, but not at three months, which suggests that most of this enlargement occurs at an early stage. The stimulation of valvular growth could represent a new strategy for the prevention of FMR.

Current Management of Patients with Severe Aortic Regurgitation.

OPINION STATEMENT: Chronic aortic regurgitation can result from various congenital and acquired anomalies and can be associated with proximal aortic disease. As the number of aortic valve procedures is growing, the incidence of post-procedural regurgitation also increases with associated morbidity. Typical evolution is characterized by a clinically silent phase of variable duration followed by a rather rapid decline with high incidence of adverse events. A challenge remains to find the optimal timing for an intervention: Patients are exposed to unnecessary surgical risks if treated prematurely, but peri- and post-operative prognosis is worse when the intervention is performed too late. Clinical evaluation and serial imaging tests can optimize the timing for intervention. Clinical follow-up should try to elucidate associated symptoms, with quantitative measurement of functional capacity as needed. Serial imaging examinations are required to identify sub-clinical left ventricular dysfunction or severe dilatation that should prompt a surgery. At least in selected cases, newer imaging modalities (MRI, 3D echocardiography) and/or biomarkers can help for the management of these patients, and more research is needed to determine if their systematic use can be beneficial. Medical treatment with vasodilators and anti-remodeling drugs can be helpful in some patients but should not replace or delay aortic valve surgery when indicated. Most patients will eventually be treated with surgical aortic valve replacement. Although possible in selected cases, transcatheter aortic valve replacement is not commonly used for patients with pure aortic regurgitation. For patients with prior aortic valve replacement and aortic regurgitation (paravalvular or intravalvular), emerging percutaneous approaches can be considered when available, especially for those at high surgical risk.