Nassir M. Thalji

Evidence, lack of evidence, controversy, and debate in the provision and performance of the surgery of acute type A aortic dissection

Acute type A aortic dissection is a lethal condition requiring emergency surgery. It has diverse presentations, and the diagnosis can be missed or delayed. Once diagnosed, decisions with regard to initial management, transfer, appropriateness of surgery, timing of operation, and intervention for malperfusion complications are necessary. The goals of surgery are to save life by prevention of pericardial tamponade or intra-pericardial aortic rupture, to resect the primary entry tear, to correct or prevent any malperfusion and aortic valve regurgitation, and if possible to prevent late dissection-related complications in the proximal and downstream aorta. No randomized trials of treatment or techniques have ever been performed, and novel therapies-particularly with regard to extent of surgery-are being devised and implemented, but their role needs to be defined. Overall, except in highly specialized centers, surgical outcomes might be static, and there is abundant room for improvement. By highlighting difficulties and controversies in diagnosis, patient selection, and surgical therapy, our over-arching goal should be to enfranchise more patients for treatment and improve surgical outcomes.

Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice

While reports suggest a single dose of senolytics may improve vasomotor function, the structural and functional impact of long‐term senolytic treatment is unknown. To determine whether long‐term senolytic treatment improves vasomotor function, vascular stiffness, and intimal plaque size and composition in aged or hypercholesterolemic mice with established disease. Senolytic treatment (intermittent treatment with Dasatinib + Quercetin via oral gavage) resulted in significant reductions in senescent cell markers (TAF+ cells) in the medial layer of aorta from aged and hypercholesterolemic mice, but not in intimal atherosclerotic plaques. While senolytic treatment significantly improved vasomotor function (isolated organ chamber baths) in both groups of mice, this was due to increases in nitric oxide bioavailability in aged mice and increases in sensitivity to NO donors in hypercholesterolemic mice. Genetic clearance of senescent cells in aged normocholesterolemic INK‐ATTAC mice phenocopied changes elicited by D+Q. Senolytics tended to reduce aortic calcification (alizarin red) and osteogenic signaling (qRT–PCR, immunohistochemistry) in aged mice, but both were significantly reduced by senolytic treatment in hypercholesterolemic mice. Intimal plaque fibrosis (picrosirius red) was not changed appreciably by chronic senolytic treatment. This is the first study to demonstrate that chronic clearance of senescent cells improves established vascular phenotypes associated with aging and chronic hypercholesterolemia, and may be a viable therapeutic intervention to reduce morbidity and mortality from cardiovascular diseases.

The prognostic impact of concomitant coronary artery bypass grafting during aortic valve surgery: implications for revascularization in the transcatheter era.

OBJECTIVE Clinicians may give greater consideration to medical management versus coronary artery bypass grafting (CABG) for coronary artery disease (CAD) at the time of aortic valve intervention. We evaluated the prognostic impact of revascularization strategy during aortic valve replacement (AVR). METHODS We studied 1308 consecutive patients with significant CAD (≥50% stenosis) undergoing AVR with or with out CABG between 2001 and 2010. Late mortality and its determinants were analyzed using multivariable Cox models. RESULTS Patients undergoing CABG (n = 1043; 18%) had more frequent angina (50% vs 26%; P < .001), left ventricular dysfunction (22% vs 14%; P = .003), advanced (>70% stenosis) CAD (85% vs 48%; P < .001), and incidence of triple-vessel/left-main CAD (44% vs 8%; P < .001). Whereas operative mortality was comparable between patients undergoing AVR plus CABG versus isolated AVR (2.9% vs 3.0%; P = .90), 5-year (72% vs 64%) and 8-year (50% vs 39%) survival was higher following CABG (P = .007). Adjusting for older age (hazard ratio [HR], 1.28 per 5 years), female sex (HR, 1.23), peripheral vascular disease (HR, 1.71), New York Heart Association functional class III to IV (HR, 1.48), and diabetes (HR, 1.50) concomitant CABG at AVR reduced late mortality risk by more than one-third (HR, 0.62, 95% confidence interval, 0.49-0.79; P < .001). CABG continued to confer a survival advantage in patients with moderate (50%-70%) (HR, 0.62; P = .02) and severe (>70%) CAD (HR, 0.62; P = .002). CONCLUSIONS In patients undergoing AVR with coexistent CAD, concomitant CABG reduces risk of late death by more than one-third, without augmenting operative mortality. This survival advantage persists in moderate (50% to 70%) and severe (>70%) CAD. These findings underline the prognostic importance of revascularization in this population and should influence decisions regarding revascularization strategy in patients undergoing transcatheter valve therapy.

Nonbiased Molecular Screening Identifies Novel Molecular Regulators of Fibrogenic and Proliferative Signaling in Myxomatous Mitral Valve Disease.

Background—Pathological processes underlying myxomatous mitral valve degeneration (MMVD) remain poorly understood. We sought to identify novel mechanisms contributing to the development of this condition. Methods and Results—Microarrays were used to measure gene expression in 11 myxomatous and 11 nonmyxomatous human mitral valves. Differential gene expression (thresholds P<0.05; fold-change >1.5) and pathway activation (Ingenuity) were confirmed using quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. Contributions of bone morphogenetic protein 4 and transforming growth factor (TGF)-&bgr;2 to differential gene expression were evaluated in vitro. Contributions of angiotensin II to differential pathway activation were examined in mice in vivo. A total of 2602 genes were differentially expressed between myxomatous and nonmyxomatous valves. Canonical TGF-&bgr; signaling was increased in MMVD because of increased ligand expression and derepression of SMA mothers against decapentaplegic 2/3 signaling and was confirmed with quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. Myxomatous valves demonstrated activation of canonical bone morphogenetic protein and Wnt/&bgr;-catenin signaling and upregulation of their common target runt-related transcription factor 2. Our data set provided transcriptional and immunohistochemical evidence for activated immune cell infiltration. In vitro treatment of mitral valve interstitial cells with TGF-&bgr;2 increased &bgr;-catenin signaling at mRNA and protein levels, suggesting interactions between TGF-&bgr;2 and Wnt signaling. In vivo infusion of mice with angiotensin II recaptured several changes in signaling pathways characteristic of human MMVD. Conclusions—These data support a new disease framework whereby activation of TGF-&bgr;2, bone morphogenetic protein 4, Wnt/&bgr;-catenin, or immune signaling plays major roles in the pathogenesis of MMVD. We propose these pathways act in a context-dependent manner to drive phenotypic changes that fundamentally differ from those observed in aortic valve disease and open novel avenues guiding future research into the pathogenesis of MMVD.

Rituximab for Non-Hodgkin's Lymphoma: A Story of Rapid Success in Translation

Translational stories range from straightforward to complex. In this commentary, the story of the rapid and successful translation of rituximab therapy for the treatment of non‐Hodgkins lymphoma (NHL) is examined. Development of this monoclonal antibody therapy began in the late 1980s. In 1994, rituximab received its first approval for the treatment of NHL by the United States Food and Drug Administration (FDA). Rituximab has since been approved for additional indications and has transformed medical practice. However, the social and political implications of these rapid successes are only beginning to become clear. In this commentary, key events in the rapid translation of rituximab from the bench to bedside are highlighted and placed into this historical framework. To accomplish this, the story of rituximab is divided into the following six topics, which we believe to be widely applicable to case studies of translation: (1) underlying disease, (2) key basic science, (3) key clinical studies in translation, (4) FDA approval process, (5) changes to medical practice, and (6) the social and political influences on translation.

Minimally Invasive Heart Valve Surgery: How and Why in 2012

Cardiac surgical procedures via traditional sternotomy are safe and effective operations performed by cardiothoracic surgeons worldwide. However, postoperative limitations in upper extremity activity during bone healing are seen as undesirable by some. Percutaneous catheter-based attempts to emulate the outcomes of traditional cardiac surgical procedures have largely fallen short of established standards of efficacy and durability. The field of minimally invasive heart valve surgery thus developed out of a need to offer smaller, better-tolerated incisions to patients while maintaining high-quality clinical outcomes. These operations are safe and effective when performed by proficient surgical teams, allowing patients to resume normal activities more rapidly. We explore current evidence supporting the practice of minimally invasive heart valve surgery in 2012 and analyze the clinical impact of these nascent surgical platforms.

Risk of Conventional Cardiac Surgery Among Patients with Severe Left Ventricular Dysfunction in the Era of Mechanical Circulatory Support

Background Despite suggestions that severe left ventricle dysfunction may warrant selection of durable mechanical circulatory support over conventional surgery, comparative studies are lacking due to incomplete characterization of patients at highest risk after conventional surgery. We sought to define subsets of patients with severe left ventricle dysfunction who are at greatest mortality risk following conventional cardiac surgery. Methods We studied 892 patients aged ≥ 18 years who underwent conventional coronary or valve surgery from 1993 to 2014, with preoperative ejection fraction ≤ 25%. Exclusions were transcatheter interventions, major concomitant procedures, active endocarditis, and prior/concurrent durable mechanical circulatory support use. Logistic and Cox regression identified determinants of early and late mortality. Results Median age was 70 years (interquartile range, 62‐76 years), 46% (n = 411) had New York Heart Association (NYHA) functional class IV symptoms, and 16% (n = 142) had undergone prior surgery. Operative mortality was 7.5%. NYHA functional class IV (odds ratio [OR], 1.88; P = .033), prior cardiac surgery (OR, 2.13; P = .017), peripheral vascular disease (OR, 2.55; P = .001), emergency status (OR, 2.68; P = .024), and intra‐aortic balloon pump use (OR, 4.95; P < .001) independently predicted operative death. Risk imparted by presence of both NYHA functional class IV symptoms and prior surgery was additive, with a 4‐fold increase in early mortality risk (OR, 3.95; P = .003). Prior surgery increased the hazard of late death by 60% (P < .001). In patients without prior surgery, late mortality was greatest in those aged ≥ 70 years (hazard ratio, 1.86; P < .001), especially if NYHA functional class IV symptoms were concurrently present (hazard ratio, 2.25; P < .001). Surgery type (coronary artery bypass graft surgery, aortic valve surgery, or mitral valve surgery) did not predict long‐term outcome. Conclusions In patients referred for conventional surgery with an ejection fraction ≤ 25%, prior cardiac surgery, and/or NYHA functional class IV symptoms—particularly in those aged ≥ 70 years—confer significant and sustained survival disadvantages. Such high‐risk subsets may benefit from durable mechanical circulatory support consideration.

Untreated aortic valve stenosis identified at the time of coronary artery bypass grafting: thresholds associated with adverse prognosis

OBJECTIVES Aortic valve replacement (AVR) for severe aortic valve stenosis (AS) is a Class I indication at the time of coronary artery bypass grafting (CABG). Management of less-than-severe AS in patients undergoing CABG is uncertain however, because the thresholds at which untreated AS impacts long-term outcome are unclear. METHODS We identified 312 patients who underwent isolated CABG between 1993 and 2006 with mild or moderate AS [aortic valve area (AVA) 1-2 cm(2)], and matched them to patients undergoing CABG alone during the same period with similar characteristics but without AS (AVA >2 cm(2)). Long-term survival after CABG and its determinants were analysed using Cox proportional hazards models with AVR as a time-dependent covariate. RESULTS Late survival was lower in patients with untreated moderate AS (12 years 23 ± 5.1%) versus mild (42 ± 3.8%) or no AS (38 ± 3.3%) (P = 0.01). Adjusting for age, ejection fraction, heart failure, creatinine, diabetes, peripheral vascular disease (PVD) and interval AVR, moderate AS independently predicted higher mortality [hazard rate (HR) 2.01, 95% confidence interval (CI) 1.49-2.73; P < 0.001]; whereas incremental risk was insignificant for patients with mild AS (HR 1.09, 95% CI 0.85-1.66; P = 0.33). Further stratification showed that highest late postoperative mortality occurred with an AVA of 1-1.25 cm(2) (adjusted HR 2.45, 95% CI 1.57-3.82; P < 0.001), while risk was intermediate with an AVA of 1.25-1.5 cm(2) (HR 1.83, 95% CI 1.28-2.61; P = 0.001). CONCLUSIONS Untreated moderate AS is an independent determinant of excess late mortality following isolated CABG, and mortality risk increases with decreasing AVA. Those with moderate-to-severe AS (AVA 1-1.25 cm(2)) have more than 2-fold greater long-term mortality compared with those without AS. These data define AS severity thresholds for clinical trials aimed at defining whether valve intervention might mitigate this risk.