Background-Little is known about the pathophysiology of myxomatous degeneration of the mitral valve, the pathological hallmark of mitral valve prolapse, associated with symptomatic mitral regurgitation, heart failure, and death. Excess transforming growth factor (TGF)- signaling is known to cause mitral valve degeneration and regurgitation in a mouse model of Marfan syndrome. We examined if TGF- signaling is dysregulated in clinical specimens of sporadic mitral valve prolapse compared with explanted nondiseased mitral valves and we tested the effects of angiotensin II receptor blockers on TGF- signaling in cultured human mitral valve cells. Methods and Results-Operative specimens, cultured valve tissues, and cultured valvular interstitial cells were obtained from patients with mitral valve prolapse undergoing mitral valve repair or from organ donors without mitral valve disease. Increased extracellular matrix in diseased valve tissue correlated with an upregulation of TGF- expression and signaling as evidenced by SMAD2/3 phosphorylation. Both TGF- ligand and signaling mediators colocalized primarily to valvular interstitial cells suggesting autocrine/paracrine activation. In cultured valve tissue, exogenous TGF- increased basal extracellular matrix production, whereas serological neutralization of TGF- inhibited disease-driven extracellular matrix overproduction. TGF--induced extracellular matrix production in cultured valvular interstitial cells was dependent on SMAD2/3 and p38 signaling and was inhibited by angiotensin II receptor blockers. Conclusions-TGF- has a profibrotic role in the pathogenesis of sporadic mitral valve prolapse. Attenuation of TGF- signaling by angiotensin II receptor blockers may represent a mechanistically based strategy to modulate the pathological progression of mitral valve prolapse in patients. (Circulation. 2012;126[suppl 1]:S189 -S197.)
Preoperative ACEi/ARB usage was associated with functional but not structural acute kidney injury. As AKI from ACEi/ARB in this setting is unclear, interventional studies testing different strategies of perioperative ACEi/ARB use are warranted.
Mitral valve (MV) dynamics depends on a force balance across the mitral leaflets, the chordae tendineae, the mitral annulus, the papillary muscles and the adjacent ventricular wall. Chordae rupture disrupts the link between the MV and the left ventricle (LV), causing mitral regurgitation (MR), the most common valvular disease. In this study, a fluid-structure interaction (FSI) modeling framework is implemented to investigate the impact of chordae rupture on the left heart (LH) dynamics and severity of MR. A control and seven chordae rupture LH models were developed to simulate a pathological process in which minimal chordae rupture precedes more extensive chordae rupture. Different non-eccentric and eccentric regurgitant jets were identified during systole. Cardiac efficiency was evaluated by the ratio of external stroke work. MV structural results showed that basal/strut chordae were the major load-bearing chordae. An increased number of ruptured chordae resulted in reduced basal/strut tension, but increased marginal/intermediate load. Chordae rupture in a specific scallop did not necessarily involve an increase in the stress of the entire prolapsed leaflet. This work represents a further step towards patient-specific modeling of pathological LH dynamics, and has the potential to improve our understanding of the biomechanical mechanisms and treatment of primary MR.
Objective Cardiac surgery is a major cause of acute kidney injury. In this setting receipt of blood transfusions appears to associate with a higher risk of AKI, as measured using serum creatinine values. We examined this association further, using urinary biomarkers of kidney injury. Methods 1210 adults underwent cardiac surgery and were divided into three groups based on the receipt of intraoperative packed red blood cell units (PRBC): no blood (n=894), ≤ 2 PRBC (n=206) and > 2 PRBC (n=110). AKI was defined as: i) Doubling of serum creatinine from the pre-operative value; ii) first post-operative urinary interleukin-18 in the 5th quintile; iii) first postoperative urinary neutrophil gelatinase-associated lipocalin in the 5th quintile. We determined the relative risk for AKI outcome according to PRBC group after adjusting for 12 pre-operative and surgical variables. Using the Sobel test for mediation analysis, we also evaluated the role of biomarkers in causing AKI through alternative pathways. Results AKI was more common in those who received >2 PRBC. In patients receiving > 2 PRBC, the adjusted RRs were 2.3 (95% CI 1.2-4.4, p 0.01), 1.36 (95% CI 1.0-1.9, p 0.05), and 1.34 (95% CI 1.0-1.8, p 0.06) for doubling of serum creatinine, urinary IL-18 in the 5th quintile (>60 pg/ml), and urinary NGAL in the 5th quintile (>102 ng/ml), respectively. Furthermore, the effect of PRBC transfusion on AKI was partially mediated by IL-18. Conclusions Receipt of two or more PRBC during cardiac surgery is associated with a greater risk of AKI defined by serum creatinine and kidney injury biomarkers.
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