Research Spotlight

Halim, S. A., F. H. Edwards, D. Dai, Z. Li, M. J. Mack, D. R. Holmes, E. M. Tuzcu, V. H. Thourani, J. K. Harrison and J. M. Brennan (2020). “Outcomes of Transcatheter Aortic Valve Replacement in Patients with Bicuspid Aortic Valve Disease: A Report from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry.” Circulation Feb 26. [Epub ahead of print].

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Background: Patients with bicuspid aortic valve (AV) stenosis were excluded from the pivotal evaluations of transcatheter AV replacement (TAVR) devices. We sought to evaluate the outcomes of TAVR in patients with bicuspid AV stenosis compared with those with tricuspid AV. Methods: We used data from the Society of Thoracic Surgeons (STS)/American College of Cardiology Transcatheter Valve Therapy Registry (November 2011-November 2018) to determine device success, procedural outcomes, post-TAVR valve performance, and in-hospital clinical outcomes (mortality, stroke, and major bleeding) according to valve morphology (bicuspid vs. tricuspid). Results were stratified by older and current (Sapien 3 and Evolut R) generation valve prostheses. Medicare administrative claims were used to evaluate mortality and stroke to 1 year among eligible individuals (>/=65 years). Results: After exclusions, there were 170,959 eligible procedures at 593 sites during the specified interval. Of these, 5,412 TAVR procedures (3.2%) were performed in bicuspid AV patients, including 3,705 with current generation devices. Compared to patients with tricuspid valves, bicuspid AV patients were younger and had a lower STS Predicted Risk of Operative Mortality (PROM) score. When current generation devices were used to treat bicuspid AV patients, device success increased (93.5 vs. 96.3, p=0.001) and the incidence of 2+ aortic insufficiency declined (14.0 vs. 2.7%, p<0.001) compared with older generation devices. With current generation devices, device success was slightly lower in the bicuspid (vs. tricuspid) AV group (96.3% in bicuspid vs. 97.4% in tricuspid, p=0.07), with a slightly higher incidence of residual moderate or severe aortic insufficiency among bicuspid AV patients (2.7% vs. 2.1%, p<0.001). A lower 1-year adjusted risk of mortality (hazard ratio 0.88, 95% confidence interval 0.78-0.99) was observed for bicuspid vs. tricuspid AV patients in the Medicare-linked cohort, while no difference was observed in the 1-year adjusted risk of stroke (hazard ratio 1.14, confidence interval 0.94-1.39). Conclusions: Using current generation devices, procedural, post-procedural, and 1-year outcomes were comparable following TAVR for bicuspid AV vs. tricuspid AV disease. With newer generation devices, TAVR is a viable treatment option for bicuspid AV patients.

Gu, S. X., V. K. Sonkar, P. B. Katare, R. Kumar, W. D. Kruger, E. Arning, T. Bottiglieri, S. R. Lentz and S. Dayal (2020). “Memantine Protects From Exacerbation of Ischemic Stroke and Blood Brain Barrier Disruption in Mild But Not Severe Hyperhomocysteinemia.” J Am Heart Assoc Feb 18;9(4): Epub 2020 Feb 13.

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Background Hyperhomocysteinemia is a risk factor for ischemic stroke; however, a targeted treatment strategy is lacking partly because of limited understanding of the causal role of homocysteine in cerebrovascular pathogenesis. Methods and Results In a genetic model of cystathionine beta synthase (CBS) deficiency, we tested the hypothesis that elevation in plasma total homocysteine exacerbates cerebrovascular injury and that memantine, a N-methyl-D-aspartate receptor antagonist, is protective. Mild or severe elevation in plasma total homocysteine was observed in Cbs+/- (6.1+/-0.3 mumol/L) or Cbs-/- (309+/-18 mumol/L) mice versus Cbs+/+ (3.1+/-0.6 mumol/L) mice. Surprisingly, Cbs-/- and Cbs+/- mice exhibited similar increases in cerebral infarct size following middle cerebral artery ischemia/reperfusion injury, despite the much higher total homocysteine levels in Cbs-/- mice. Likewise, disruption of the blood brain barrier was observed in both Cbs+/- and Cbs-/- mice. Administration of the N-methyl-D-aspartate receptor antagonist memantine protected Cbs+/- but not Cbs-/- mice from cerebral infarction and blood brain barrier disruption. Our data suggest that the differential effect of memantine in Cbs+/- versus Cbs-/- mice may be related to changes in expression of N-methyl-D-aspartate receptor subunits. Cbs-/-, but not Cbs+/- mice had increased expression of NR2B subunit, which is known to be relatively insensitive to homocysteine. Conclusions These data provide experimental evidence that even a mild increase in plasma total homocysteine can exacerbate cerebrovascular injury and suggest that N-methyl-D-aspartate receptor antagonism may represent a strategy to prevent reperfusion injury after acute ischemic stroke in patients with mild hyperhomocysteinemia.

Gelfand, J. M., D. B. Shin, K. C. Duffin, A. W. Armstrong, A. Blauvelt, S. K. Tyring, A. Menter, S. Gottlieb, B. N. Lockshin, E. L. Simpson, F. Kianifard, R. P. Sarkar, E. Muscianisi, J. Steadman, M. A. Ahlman, M. P. Playford, A. A. Joshi, A. K. Dey, T. J. Werner, A. Alavi and N. N. Mehta (2020). “A Randomized Placebo Controlled Trial of Secukinumab on Aortic Vascular Inflammation in Moderate to Severe Plaque Psoriasis (VIP-S).” J Invest Dermatol Feb 20. [Epub ahead of print].

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BACKGROUND: Psoriasis, a chronic immune-mediated disease, is associated with an increased risk of cardiovascular events and mortality. Secukinumab selectively neutralizes IL-17A and has demonstrated high efficacy with a favorable safety profile in various psoriatic disease manifestations. TRIAL DESIGN AND METHODS: Subsequent to the 12-week randomized, placebo-controlled, double-blind treatment period, moderate-to-severe psoriasis patients received secukinumab for 40 weeks. Vascular inflammation using FDG-PET/CT imaging and blood-based cardiometabolic was assessed at week 0, 12, and 52. RESULTS: The difference in change in aortic inflammation from baseline to Week 12 for secukinumab (N=46) versus placebo (N=45) was -0.053 (95% CI: -0.169, 0.064; P=0.37). Small increases in total cholesterol, LDL, and LDL particles, but no changes in markers of inflammation, adiposity, insulin resistance, or predictors of diabetes, were observed with secukinumab treatment compared with placebo. At Week 52, reductions in TNF-alpha (P=0.0063) and ferritin (P=0.0354), and an increase in fetuin A (P=0.0024), were observed with secukinumab treatment compared to baseline. No significant changes in aortic inflammation or markers of advanced lipoprotein characterization, adiposity, or insulin resistance were observed with secukinumab treatment compared to baseline. CONCLUSION: Secukinumab exhibited a neutral impact on aortic vascular inflammation and biomarkers of cardiometabolic disease after 52 weeks of treatment.

Edgerton, J. R. (2020). “Current State of Surgical Left Atrial Appendage Exclusion: How and When.” Card Electrophysiol Clin 12(1): 109-115.

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Left atrial appendage exclusion is efficacious for stroke prophylaxis in patients with atrial fibrillation. Surgical excision provides reliable left atrial appendage exclusion, whereas surgical occlusion does not. Specifically, 2-layer internal suture ligation has a high failure rate. Left atrial appendage exclusion concomitant to another cardiac surgical procedure is indicated in patients with atrial fibrillation but not in patients without baseline atrial fibrillation. Studies currently underway will further define the role of concomitant surgical left atrial appendage exclusion, especially for the population without baseline atrial fibrillation but at high risk of developing postoperative atrial fibrillation.

Doyle, J. D., L. Beacham, E. T. Martin, H. K. Talbot, A. Monto, M. Gaglani, D. B. Middleton, F. P. Silveira, R. K. Zimmerman, E. Alyanak, E. R. Smith, B. L. Flannery, M. Rolfes and J. M. Ferdinands (2020). “Relative and absolute effectiveness of high-dose and standard-dose influenza vaccine against influenza-related hospitalization among older adults – United States, 2015-2017.” Clin Infect Dis Feb 18. [Epub ahead of print].

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BACKGROUND: Seasonal influenza causes substantial morbidity and mortality in older adults. High-dose inactivated influenza vaccine (HD-IIV), with increased antigen content compared to standard-dose influenza vaccines (SD-IIV), is licensed for use in people aged >/=65 years. We sought to evaluate the effectiveness of HD-IIV and SD-IIV for prevention of influenza-associated hospitalizations. METHODS: Hospitalized patients with acute respiratory illness were enrolled in an observational vaccine effectiveness study at eight hospitals in the United States Hospitalized Adult Influenza Vaccine Effectiveness Network during the 2015-2016 and 2016-2017 influenza seasons. Enrolled patients were tested for influenza, and receipt of influenza vaccine by type was recorded. Effectiveness of SD-IIV and HD-IIV was estimated using a test-negative design (comparing odds of influenza among vaccinated and unvaccinated patients). Relative effectiveness of SD-IIV and HD-IIV was estimated using logistic regression. RESULTS: Among 1487 enrolled patients aged >/=65 years, 1107 (74%) were vaccinated; 622 (56%) received HD-IIV and 485 (44%) received SD-IIV. Overall, 277 (19%) tested positive for influenza, including 98 (16%) who received HD-IIV, 87 (18%) who received SD-IIV, and 92 (24%) who were unvaccinated. After adjusting for confounding variables, effectiveness of SD-IIV was 6% (95% confidence interval [CI] -42%, 38%) and that of HD-IIV was 32% (95%CI -3%, 54%), for a relative effectiveness of HD-IIV versus SD-IIV of 27% (95%CI -1%, 48%). CONCLUSIONS: During two U.S. influenza seasons, vaccine effectiveness was low to moderate for prevention of influenza hospitalization among adults aged >/=65 years. High-dose vaccine offered greater effectiveness. None of these findings were statistically significant.