Cardiology

Packer, M. (2020). “Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium-glucose cotransporter 2 inhibitors.” Eur J Heart Fail Feb 10. [Epub ahead of print].

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In five large-scale trials involving >40 000 patients, sodium-glucose cotransporter 2 (SGLT2) inhibitors decreased the risk of serious heart failure events by 25-40%. This effect cannot be explained by control of hyperglycaemia, since it is not observed with antidiabetic drugs with greater glucose-lowering effects. It cannot be attributed to ketogenesis, since it is not causally linked to ketone body production, and the benefit is not enhanced in patients with diabetes. The effect cannot be ascribed to a natriuretic action, since SGLT2 inhibitors decrease natriuretic peptides only modestly, and they reduce cardiovascular death, a benefit that diuretics do not possess. Although SGLT2 inhibitors increase red blood cell mass, enhanced erythropoiesis does not favourably influence the course of heart failure. By contrast, experimental studies suggest that SGLT2 inhibitors may reduce intracellular sodium, thereby preventing oxidative stress and cardiomyocyte death. Additionally, SGLT2 inhibitors induce a transcriptional paradigm that mimics nutrient and oxygen deprivation, which includes activation of adenosine monophosphate-activated protein kinase, sirtuin-1, and/or hypoxia-inducible factors-1alpha/2alpha. The interplay of these mediators stimulates autophagy, a lysosomally-mediated degradative pathway that maintains cellular homeostasis. Autophagy-mediated clearance of damaged organelles reduces inflammasome activation, thus mitigating cardiomyocyte dysfunction and coronary microvascular injury. Interestingly, the action of hypoxia-inducible factors-1alpha/2alpha to both stimulate erythropoietin and induce autophagy may explain why erythrocytosis is strongly correlated with the reduction in heart failure events. Therefore, the benefits of SGLT2 inhibitors on heart failure may be mediated by a direct cardioprotective action related to modulation of pathways responsible for cardiomyocyte homeostasis.

Murdoch, D. J., J. Sathananthan, M. Hensey, M. C. Alu, Y. Liu, A. Crowley, D. Wood, A. Cheung, J. Ye, T. Feldman, R. T. Hahn, W. A. Jaber, M. J. Mack, S. C. Malaisrie, M. B. Leon and J. G. Webb (2020). “Mitral regurgitation in patients undergoing transcatheter aortic valve implantation for degenerated surgical aortic bioprosthesis: Insights from PARTNER 2 Valve-in-Valve Registry.” Catheter Cardiovasc Interv Mar 2. [Epub ahead of print].

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BACKGROUND: Valve-in-valve (VIV) treatment with transcatheter aortic valve replacement (TAVR) is a viable option for patients with failing aortic bioprosthetic valves. Optimal management of those with concomitant mitral regurgitation (MR) remains undetermined. Therefore, we sought to assess the implications of concomitant MR in patients undergoing VIV-TAVR. METHODS AND RESULTS: The PARTNER 2 VIV registry enrolled patients with degenerated surgical aortic bioprosthesis at high risk for reoperation. Patients with core-laboratory echocardiographic assessment of MR were analyzed; severe MR was excluded. We compared patients with less-than-or-equal-to mild MR versus moderate MR and assessed changes in MR severity and clinical outcomes. A total of 339 patients (89 initial registry, 250 continued access) underwent VIV procedures; mean age 79.0 +/- 10.2 years, mean Society of Thoracic Surgeon score 8.9 +/- 4.5%. At baseline, 228/339 (67.3%) had less-than-or-equal-to mild MR and 111/339 (32.7%) had moderate MR. In paired analysis, there was significant improvement in greater-than-or-equal-to moderate MR from baseline to 30 days (32.6% vs. 14.5%, p < .0001 [n = 304]), and no significant change between 30 days and 1 year (13.4% vs. 12.1%, p = .56 [n = 224]) or 1 year and 2 years (11.0% vs. 10.4%, p = .81 [n = 182]). There was no difference in death or stroke between less-than-or-equal-to mild MR and moderate MR at 30 days (4.0% vs. 7.2%, p = .20), 1 year (15.5% vs. 15.3%, p = .98) or 2 years (26.5% vs. 23.5%, p = .67). CONCLUSION: Moderate concomitant MR tends to improve with VIV-TAVR, and was not a predictor of long-term adverse outcomes in this cohort. In selected patients undergoing VIV-TAVR, it may be appropriate to conservatively manage concomitant MR. ClinicalTrials.gov NCT# 03225001.

Mack, M. J. and L. Svensson (2020). “Why Does More SAVR Make Better TAVR?” JACC Cardiovasc Interv 13(3): 344-345.

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It has been well documented that there is a direct correlation between institutional procedural volume of transcatheter aortic valve replacement (TAVR) and the outcomes of patients undergoing TAVR. It has also been clearly demonstrated that a center’s surgical aortic valve replacement (SAVR) volume is directly related to better SAVR outcomes. However, does the same volume-outcome relationship exist between an institution’s SAVR volume and the outcomes of TAVR and if so, why does it matter. In this issue of JACC: Cardiovascular Interventions, Hirji et al. address this first question by comparing SAVR volume with corresponding TAVR outcomes. (Excerpt from text, n.p.; no abstract available.)

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.

Dangas, G. D., J. G. P. Tijssen, J. Wohrle, L. Sondergaard, M. Gilard, H. Mollmann, R. R. Makkar, H. C. Herrmann, G. Giustino, S. Baldus, O. De Backer, A. H. C. Guimaraes, L. Gullestad, A. Kini, D. von Lewinski, M. Mack, R. Moreno, U. Schafer, J. Seeger, D. Tchetche, K. Thomitzek, M. Valgimigli, P. Vranckx, R. C. Welsh, P. Wildgoose, A. A. Volkl, A. Zazula, R. G. M. van Amsterdam, R. Mehran and S. Windecker (2020). “A Controlled Trial of Rivaroxaban after Transcatheter Aortic-Valve Replacement.” New England Journal of Medicine 382(2): 120-129.

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BACKGROUND: Whether the direct factor Xa inhibitor rivaroxaban can prevent thromboembolic events after transcatheter aortic-valve replacement (TAVR) is unclear. METHODS: We randomly assigned 1644 patients without an established indication for oral anticoagulation after successful TAVR to receive rivaroxaban at a dose of 10 mg daily (with aspirin at a dose of 75 to 100 mg daily for the first 3 months) (rivaroxaban group) or aspirin at a dose of 75 to 100 mg daily (with clopidogrel at a dose of 75 mg daily for the first 3 months) (antiplatelet group). The primary efficacy outcome was the composite of death or thromboembolic events. The primary safety outcome was major, disabling, or life-threatening bleeding. The trial was terminated prematurely by the data and safety monitoring board because of safety concerns. RESULTS: After a median of 17 months, death or a first thromboembolic event (intention-to-treat analysis) had occurred in 105 patients in the rivaroxaban group and in 78 patients in the antiplatelet group (incidence rates, 9.8 and 7.2 per 100 person-years, respectively; hazard ratio with rivaroxaban, 1.35; 95% confidence interval [CI], 1.01 to 1.81; P = 0.04). Major, disabling, or life-threatening bleeding (intention-to-treat analysis) had occurred in 46 and 31 patients, respectively (4.3 and 2.8 per 100 person-years; hazard ratio, 1.50; 95% CI, 0.95 to 2.37; P = 0.08). A total of 64 deaths occurred in the rivaroxaban group and 38 in the antiplatelet group (5.8 and 3.4 per 100 person-years, respectively; hazard ratio, 1.69; 95% CI, 1.13 to 2.53). CONCLUSIONS: In patients without an established indication for oral anticoagulation after successful TAVR, a treatment strategy including rivaroxaban at a dose of 10 mg daily was associated with a higher risk of death or thromboembolic complications and a higher risk of bleeding than an antiplatelet-based strategy. (Funded by Bayer and Janssen Pharmaceuticals; GALILEO ClinicalTrials.gov number, NCT02556203.).