Arnar Geirsson

Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis

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.

Trends in Aortic Valve Replacement for Elderly Patients in the United States, 1999-2011

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 PARTICIPANTS A 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 MEASURES Procedure rates for surgical AVR alone and with coronary artery bypass graft (CABG) surgery, 30-day and 1-year mortality, and 30-day readmission rates. RESULTS The 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 RELEVANCE Between 1999 and 2011, the rate of surgical AVR for elderly patients in the United States increased and outcomes improved substantially. Medicare data preclude the identification of the causes of the findings and the trends in procedure rates and outcomes cannot be causally linked. Nevertheless, the findings may be a useful benchmark for outcomes with surgical AVR for older patients eligible for surgery considering newer transcatheter treatments.

Observational study of mortality risk stratification by ischemic presentation in patients with acute type A aortic dissection: the Penn classification

Background Acute type A aortic dissection is a surgical emergency, with an operative mortality as high as 25%. Ischemia is a known predictor of mortality. We tested the efficacy of a classification system—the Penn classification, which is based on ischemic pattern at clinical presentation—to stratify operative mortality risk and identify high-risk groups of patients for further intervention and study.Methods In this prospective observational study, patients underwent a standard aortic dissection repair protocol at the University of Pennsylvania, Philadelphia, PA, from 1993 to 2004. Patients were classified as having no ischemia, branch vessel malperfusion with localized organ ischemia, generalized ischemia with circulatory collapse, with or without cardiac involvement, or a combination of localized and generalized ischemia.Results The cohort comprised 221 patients. The mean age was 61.6 (± 14.8) years and 66.5% were male. At presentation 57.9% of patients had no ischemia, 17.6% had localized ischemia, 15.4% had generalized ischemia, and 9.0% had both localized and generalized ischemia. Overall, 28 (12.7%) patients died during the perioperative period. All-cause mortality differed significantly between groups (no ischemia 3.1%, localized ischemia 25.6%, generalized ischemia 17.6%, combined ischemia 40.0%), yielding an overall 8.3-fold difference for no compared with any ischemia (3.1% versus 25.8%, P = 0.0001). Ischemic presentations together accounted for 85.7% of all deaths.Conclusion 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.

Modulation of Transforming Growth Factor-β Signaling and Extracellular Matrix Production in Myxomatous Mitral Valves by Angiotensin II Receptor Blockers

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)-&bgr; signaling is known to cause mitral valve degeneration and regurgitation in a mouse model of Marfan syndrome. We examined if TGF-&bgr; 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-&bgr; 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-&bgr; expression and signaling as evidenced by SMAD2/3 phosphorylation. Both TGF-&bgr; ligand and signaling mediators colocalized primarily to valvular interstitial cells suggesting autocrine/paracrine activation. In cultured valve tissue, exogenous TGF-&bgr; increased basal extracellular matrix production, whereas serological neutralization of TGF-&bgr; inhibited disease-driven extracellular matrix overproduction. TGF-&bgr;-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-&bgr; has a profibrotic role in the pathogenesis of sporadic mitral valve prolapse. Attenuation of TGF-&bgr; signaling by angiotensin II receptor blockers may represent a mechanistically based strategy to modulate the pathological progression of mitral valve prolapse in patients.

Endograft Collapse after Thoracic Endovascular Aortic Repair

Purpose: To provide insight into the causes, timing, and optimal management of endograft collapse after thoracic endovascular aortic repair (TEVAR). Methods: A comprehensive review was conducted of all published cases of endograft collapse after TEVAR identified using Medline, Cochrane Library Central, and EMBASE. In total, 32 articles describing 60 patients (45 men; mean age 40.6 ±17.2 years, range 17–78) with endograft collapse were included. All data were extracted from the articles and systematically entered into a database for meta-analysis. Results: In the 60 cases of endograft collapse, TEVAR had most commonly been applied to repair traumatic thoracic aortic injuries (39, 65%), followed by acute and chronic type B aortic dissections (9, 15%). The median time interval between TEVAR and diagnosis of endograft collapse was 15 days (range 1 day to 79 months). On average, the collapsed endografts were oversized by 26.7%±12.0% (range 8.3%–60.0%). Excessive oversizing was reported as the primary cause of endograft collapse in 20%, and a small radius of curvature of the aortic arch was responsible for 48% of the cases. The 30-day mortality was 8.3%, and the freedom from procedure-related death at 3 years after diagnosis of stent-graft collapse was 83.1% for asymptomatic patients compared with 72.7% for patients who had symptoms at diagnosis (p=0.029). Conclusion: Endograft collapse typically occurs shortly after TEVAR, most frequently after endovascular repair of traumatic aortic injury. A high level of suspicion for endograft collapse in the first month after TEVAR, as well as further improvement of current endovascular devices, may be required to improve the long-term outcomes of patients after TEVAR.

Oesophageal perforations in Iceland : a whole population study on incidence, aetiology and surgical outcome

BACKGROUND Oesophageal perforation is a rare but life-threatening condition with a significant morbidity and mortality. In this retrospective, nationwide study, the results of oesophageal perforation are reported for a well defined cohort, with special emphasis on the incidence, aetiology and results of surgical treatment. MATERIAL AND METHODS 29 consecutive patients (16 males) were diagnosed with perforation of the oesophagus at Landspitali University Hospital between 1980 and 2007. Patients had a mean age of 61 years (range: 7 months-90 years). Type of surgery, complications and survival were recorded. Average follow-up was 76 months. RESULTS Age-standardised incidence of oesophageal perforation was 3.1/1,000,000 per year during the study period. Out of 29 patients diagnosed with oesophageal perforation, the diagnosis was missed in 5 cases (17%) and first made at autopsy. Iatrogenic injury was the most frequent cause (52%), followed by spontaneous perforation (24%) and foreign body ingestion (17%). Thoracic perforations were seen in 73% of patients, and 14 patients had an underlying oesophageal disease. Nineteen patients were treated surgically, in 16 cases with drainage of the mediastinum via thoracotomy and insertion of chest tubes. The median time from perforation to surgery was 6.5 h and median length of hospital stay was 15 days (range: 9-83). All surgically treated patients survived surgery, and the 5-year overall survival rate was 69%. CONCLUSION More than half of all oesophageal injuries in Iceland are caused by a iatrogenic injury. Mortality is significant and is related to a missed diagnosis. Patients treated surgically all survived surgery; however, complications were frequent and their hospital stay was long.

miR-1 mediated suppression of Sorcin regulates myocardial contractility through modulation of Ca2+ signaling.

MicroRNAs are negative gene regulators and play important roles in cardiac development and disease. As evident by cardiomyopathy following cardiac-specific Dicer knockdown they also are required for maintaining normal cardiac contractile function but the specific role of miR-1 in the process is poorly understood. To characterize the role of miR-1 in particular and to identify its specific targets we created a tamoxifen-inducible, cardiac-specific Dicer knockdown mouse and demonstrated that Dicer downregulation results in a dramatic and rapid decline in cardiac function concurrent with significantly reduced levels of miR-1. The importance of miR-1 was established by miR-1 antagomir treatment of wild-type mice, which replicated the cardiac-specific Dicer knockdown phenotype. Down-regulation of miR-1 was associated with up-regulation of its predicted target Sorcin, an established modulator of calcium signaling and excitation-contraction coupling, subsequently verified as a miR-1 target with luciferase constructs. siRNA-mediated knockdown of Sorcin effectively rescued the cardiac phenotypes after Dicer or miR-1 knockdown affirming Sorcin as a critical mediator of the acute cardiomyopathy observed. The regulatory relationship between miR-1 and Sorcin was further confirmed in cultured mouse cardiomyocytes where modulation of miR-1 was associated with discordant Sorcin levels and dysregulation of calcium signaling. Pathological relevance of our findings included decreased miR-1 and increased Sorcin expression in end-stage cardiomyopathy. These findings demonstrate the importance of miR-1 in cardiac function and in the pathogenesis of heart failure via Sorcin-dependent calcium homeostasis.

Class II transactivator promoter activity is suppressed through regulation by a trophoblast noncoding RNA.

Background. Trophoblasts lack expression of all classic major histocompatibility complex (MHC) antigens. Determination of the mechanism involved could provide insight into selective gene suppression and allograft tolerance. Suppression of class II expression in trophoblasts is secondary to dominant negative trans-acting factors that suppress class II transactivator (CIITA) transcription. We recently described a trophoblast-derived noncoding RNA (TncRNA) that suppresses class II expression. We examined the effects of TncRNA on the CIITA promoter, CIITA, and MHC class II expression. Methods. HeLa clones stably transfected with TncRNA were analyzed for MHC class II and CIITA expression by fluorescence-activated cell sorting, Northern blots, and quantitative polymerase chain reaction. Activity and functional dissection of CIITA promoter IV (pIV) was assessed by transient co-transfection of promoter-reporter constructs. Methylation of pIV was assessed by Southern blots, fluorescence-activated cell sorting, and quantitative polymerase chain reaction. Results. TncRNA suppressed interferon-&ggr;–induced human leukocyte antigen-DR and CIITA expression in HeLa cells. The mechanism involves inhibition of CIITA pIV through a defined inhibitory domain on the promoter. The mechanism does not involve methylation of the promoter. Conclusions. A novel method of CIITA suppression is described where a noncoding RNA selectively mediates the suppression of CIITA pIV possibly by complementary RNA-DNA binding to an inhibitory domain on the promoter. Selective suppression of MHC class II could have important implications in allograft tolerance and in developing class II-deficient cells or tissues for the purpose of transplantation or drug delivery systems.

Trends in Aortic Dissection Hospitalizations, Interventions, and Outcomes Among Medicare Beneficiaries in the United States, 2000–2011

Background—The epidemiology of aortic dissection (AD) has not been well described among older persons in the United States. It is not known whether advancements in AD care over the last decade have been accompanied by changes in outcomes. Methods and Results—The Inpatient Medicare data from 2000 to 2011 were used to determine trends in hospitalization rates for AD. Mortality rates were ascertained through corresponding vital status files. A total of 32 057 initial AD hospitalizations were identified. The overall hospitalization rate for AD remained unchanged at 10 per 100 000 person-years. For 30-day and 1-year mortality associated with AD, the observed rate decreased from 31.8% to 25.4% (difference, 6.4%; 95% confidence interval [CI], 6.2–6.5; adjusted, 6.4%; 95% CI, 5.7–6.9) and from 42.6% to 37.4% (difference, 5.2%; 95% CI, 5.1–5.2; adjusted, 6.2%; 95% CI, 5.3–6.7), respectively. For patients undergoing surgical repair for type A dissections, the observed 30-day mortality decreased from 30.7% to 21.4% (difference, 9.3%; 95% CI, 8.3–10.2; adjusted, 7.3%; 95% CI, 5.8–7.8) and the observed 1-year mortality decreased from 39.9% to 31.6% (difference, 8.3%; 95% CI, 7.5–9.1%; adjusted, 8.2%; 95% CI, 6.7–9.1). The 30-day mortality decreased from 24.9% to 21% (difference, 3.9%; 95% CI, 3.5–4.2; adjusted, 2.9%; 95% CI, 0.7–4.4) and 1-year decreased from 36.4% to 32.5% (difference, 3.9%; 95% CI, 3.3–4.3; adjusted, 3.9%; 95% CI, 2.5–6.3) for surgical repair of type B dissection. Conclusions—Although AD hospitalization rates remained stable, improvement in mortality was noted, particularly in patients undergoing surgical repair.

Human trophoblast noncoding RNA suppresses CIITA promoter III activity in murine B-lymphocytes

Trophoblasts lack expression of all classical MHC antigens. Determination of the mechanism involved could provide insight into selective gene suppression and allograft tolerance. Suppression of class II expression in trophoblasts is secondary to dominant negative trans-acting factors that suppress class II transactivator (CIITA) transcription. We recently described a trophoblast-derived noncoding RNA (TncRNA) that suppresses class II expression. Murine B-cells CH27 were stably transfected with TncRNA and analyzed for MHC class II and CIITA expression by FACS and Northern blots. Functional assessment of CIITA promoter III (pIII) was performed by transient transfection of promoter-reporter constructs. Methylation of pIII was assessed by Southern blots and FACS. TncRNA suppressed constitutive I-Ak and CIITA expression in murine B-cells CH27. The mechanism involves inhibition of CIITA pIII activity. The mechanism does not involve methylation of the promoter.