TGF-β is essential for vascular development; however, excess TGF-β signaling promotes thoracic aortic aneurysm and dissection in multiple disorders, including Marfan syndrome. Since the pathology of TGF-β overactivity manifests primarily within the arterial media, it is widely assumed that suppression of TGF-β signaling in vascular smooth muscle cells will ameliorate aortic disease. We tested this hypothesis by conditional inactivation of Tgfbr2, which encodes the TGF-β type II receptor, in smooth muscle cells of postweanling mice. Surprisingly, the thoracic aorta rapidly thickened, dilated, and dissected in these animals. Tgfbr2 disruption predictably decreased canonical Smad signaling, but unexpectedly increased MAPK signaling. Type II receptor-independent effects of TGF-β and pathological responses by nonrecombined smooth muscle cells were excluded by serologic neutralization. Aortic disease was caused by a perturbed contractile apparatus in medial cells and growth factor production by adventitial cells, both of which resulted in maladaptive paracrine interactions between the vessel wall compartments. Treatment with rapamycin restored a quiescent smooth muscle phenotype and prevented dissection. Tgfbr2 disruption in smooth muscle cells also accelerated aneurysm growth in a murine model of Marfan syndrome. Our data indicate that basal TGF-β signaling in smooth muscle promotes postnatal aortic wall homeostasis and impedes disease progression.

The occurrence of malperfusion in patients with acute type A dissection is associated with significant increased risk of in-hospital mortality and complications. Additional revascularization is generally needed in patients with coronary malperfusion and ileofemoral malperfusion. Patients presenting with cardiac and cerebral malperfusions have a high hospital mortality and preoperative cerebral malperfusion is associated with dismal long-term survival.

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The incidence of ATAD was 2.53/100 000/year and remained constant throughout the study, contradicting recent perceptions of a rising incidence. ATAD, type A in particular, remains a highly lethal condition: Over half of all patients die within 30 days of the index event. A reduced 30-day mortality rate and an increased long-term survival rate indicate improved overall outcomes in patients with this complex condition.

The Penn classification of acute type A aortic dissection enabled stratification of patients by operative mortality risk. The system requires further validation, but might facilitate new ways to analyze mortality data for this disorder.

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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.)

ortic valve disease in the United States is a major cardiovascular problem that is likely to grow as the population ages. [1][2][3][4][5] Aortic valve replacement is the standard treatment even for very elderly patients despite its risks in this age group. 6 With transcatheter aortic valve replacement emerging as a less invasive option, 7-9 contemporary data from real-world practice are needed to provide a perspective on the outcomes that are being achieved with surgery.Changes in practice during the past decade are partly due to growing recognition that the benefits of aortic valve replacement extend to extremes in patient age. 10,11 There is also a recommendation for consideration of earlier, preemptive aortic valve replacement in selected asymptomatic patients 12 and strong guidance that bioprostheses rather than mechanical valves be used for patients 65 years or older. 13,14 There is also uncertainty about the benefit of performing coronary artery bypass graft (CABG) surgery during aortic valve replacement in patients with stable coronary disease. 8,15,16 Previous studies have indicated that rates of aortic valve replacement are increasing and outcomes are improving [17][18][19][20] but do not provide population-based rates and long-term follow-up. [17][18][19][20] We therefore studied aortic valve replacement among Medicare fee-for-service beneficiaries between 1999 and 2011. We calculated trends in rates of surgical aortic valve replacement and outcomes defined as mortality, readmission, and length of stay. In addition, we compared the outcomes of pa-IMPORTANCE There is a need to describe contemporary outcomes of surgical aortic valve replacement (AVR) as the population ages and transcatheter options emerge.OBJECTIVE To assess procedure rates and outcomes of surgical AVR over time. DESIGN, SETTING, AND PARTICIPANTSA serial cross-sectional cohort study of 82 755 924 Medicare fee-for-service beneficiaries undergoing AVR in the United States between 1999 and 2011. MAIN OUTCOMES AND MEASURESProcedure rates for surgical AVR alone and with coronary artery bypass graft (CABG) surgery, 30-day and 1-year mortality, and 30-day readmission rates. RESULTSThe AVR procedure rate increased by 19 (95% CI, 19-20) procedures per 100 000 person-years over the 12-year period (P<.001), with an age-, sex-, and race-adjusted rate increase of 1.6% (95% CI, 1.0%-1.8%) per year. Mortality decreased at 30 days (absolute decrease, 3.4%; 95% CI, 3.0%-3.8%; adjusted annual decrease, 4.1%; 95% CI, 3.7%-4.4%) per year and at 1 year (absolute decrease, 2.6%; 95% CI, 2.1%-3.2%; adjusted annual decrease, 2.5%; 95% CI, 2.3%-2.8%). Thirty-day all-cause readmission also decreased by 1.1% (95% CI, 0.9%-1.3%) per year. Aortic valve replacement with CABG surgery decreased, women and black patients had lower procedure and higher mortality rates, and mechanical prosethetic implants decreased, but 23.9% of patients 85 years and older continued to receive a mechanical prosthesis in 2011. CONCLUSIONS AND RELEVANCEBetween 1999 and 2011, the rate of ...