Background: A landmark genome-wide association study has linked mutations in the plasma lipoprotein complex lipoprotein(a) [Lp(a)] and aortic stenosis. We attempted to determine whether Lp(a) is a key upstream mediator of aortic stenosis. Methods: Male, Lp(a) transgenic (N=10) and control mice (N=10) were fed a high cholesterol diet for 6 weeks, then hearts were sectioned for histological analysis. Human stenosis (N=8) and non-stenotic (N=7) aortic valve leaflets were obtained intraoperatively and submitted for histologic and immunohistochemical analyses. All histological sections were semi-quantitatively graded in a blinded manner (0-3/3+ units). Results: Aortic valves from Lp(a) transgenic mice fed a high-cholesterol diet demonstrated significant aortic valve changes including fibrosis (2.0/4 vs 0.5/4), calcification (1.9.4 vs 0.1/4) units, angiogenesis (1.1/4 vs 0.3/4) and inflammatory infiltration (1.0 vs 0.1/4) compared with control aortic valves (all p<0.001). Human stenotic aortic valve leaflets expressed greater Lp(a) (2.4/4 vs 1.7/4) in areas of fibrosis, inflammatory infiltration and angiogenesis, compared with non-stenotic aortic valve leaflets (p=<0.005) Conclusion: Our proof-of-concept studies offer evidence for a potential causative role of Lp(a) as a trigger of aortic stenosis. Further work is needed to confirm these results. Therapeutic strategies targeting Lp(a) levels may serve as a novel strategy to limit progressive calcification in aortic stenosis.

Background and Aim: The P2Y12 platelet receptor inhibitor ticagrelor is widely used in patients following acute coronary syndromes or in those who have received coronary stents. Bentracimab is a monoclonal antibody-based reversal agent that is being formally evaluated in a Phase 3 clinical trial. Here, we probe the knowledge, attitudes, and practice patterns of cardiac surgeons regarding their perioperative management of ticagrelor and potential application of a ticagrelor reversal agent. Methods: A questionnaire was developed by a working group of cardiac surgeons to inquire into participants’ practices and beliefs regarding ticagrelor and disseminated to practicing Canadian cardiac surgeons. Results: A total of 70 Canadian cardiac surgeons participated. Bleeding risk was identified as the most significant consideration when surgically revascularizing ticagrelor-treated patients (90%). There is variability in the duration of withholding ticagrelor prior to coronary artery bypass graft procedure in a stable patient; 44.3% wait 3 days and 32.9% wait 4 days or longer. Currently, 14.3% of cardiac surgeons prophylactically give platelet transfusions and/or fresh frozen plasma intraoperatively following protamine infusion in patients who have recently received ticagrelor. Interestingly, 47.1% of surveyed surgeons were aware of a reversal agent for ticagrelor, 91.4% of cardiac surgeons would consider utilizing a ticagrelor reversal agent if available, and 51.4% acknowledged that the introduction of such an agent would be a major advance in clinical practice. Conclusions: The present survey identified ticagrelor-related bleeding as a major concern for cardiac surgeons. Surgeons recognized the significant unmet need that a ticagrelor reversal agent would address.

Abstract Background: Many patients with end stage kidney disease (ESKD) have valvular heart disease requiring surgery. The optimal prosthetic valve is not established in this population. We performed a systematic review and meta-analysis assessing outcomes of patients with dialysis-dependent ESKD who received mechanical or bioprosthetic valves. Methods: We searched Cochrane CENTRAL, MEDLINE, and EMBASE from inception to January 2020. We performed screening, full-text assessment, risk of bias, and data-collection independently and in duplicate. We evaluated risk of bias using the ROBINS-I tool and certainty in evidence with GRADE. Data were pooled using a random-effects model. Results: We identified 28 observational studies (n=9857; 6680 mechanical and 3717 bioprosthetic) with a median follow-up of 3.45 years. Due to confounding, 22 studies were at “high” and one at “critical” risk of bias. Certainty in evidence for all outcomes, except for bleeding, was very-low. Mechanical valves were associated with reduced mortality at 30 days (RR0.79, 95%CI[0.65,0.97], I2=0, absolute effect 27 fewer deaths per 1000) and at ≥ 6 years (mean 9.7 years, RR0.83, 95%CI[0.72,0.96], I2=79%, absolute effect 145 fewer deaths per 1000), but increased bleeding (RR2.46, 95%CI[1.35,4.48], I2=69% absolute effect 113 more events per 1000) and stroke (RR1.53, 95%CI[1.13,2.07], I2=0%, absolute effect 21 more events per 1000). Conclusion: Mechanical valves are associated with reduced mortality, but increased risks of bleeding and stroke. Given very-low certainty for mortality and stroke, patients and clinicians may choose a prosthetic valve based on factors such as bleeding risk and valve longevity.