Landolfo, Carolyn

Background: Transcatheter aortic valve replacement (TAVR) is now an approved alternative to surgical aortic valve replacement for the treatment of severe aortic stenosis. As the clinical adoption of TAVR expands, it remains important to identify predictors of mortality after TAVR. We aimed to evaluate the impact of sex differences in aortic valve calcium score (AVCS) on long-term mortality following TAVR in a large patient sample. Methods: We included consecutive patients who successfully underwent TAVR for treatment of severe native aortic valve stenosis from June 2010 to May 2021 across all US Mayo Clinic sites with follow-up through July 2021. AVCS values were obtained from preoperative computed tomography of the chest. Additional clinical data were abstracted from medical records. Kaplan-Meier curves and Cox-proportional hazard regression models were employed to evaluate the effect of AVCS on long-term mortality. Results: A total of 2543 patients were evaluated in the final analysis. Forty-one percent were women, median age was 82 years (Q1: 76, Q3: 86), 18.4% received a permanent pacemaker following TAVR, and 88.5% received a balloon expandable valve. We demonstrate an increase in mortality risk with higher AVCS after multivariable adjustment ( P <0.001). When stratified by sex, every 500-unit increase in AVCS was associated with a 7% increase in mortality risk among women (adjusted hazard ratio, 1.07 [95% CI, 1.02–1.12]) but not in men. Conclusions: We demonstrate a notable sex difference in the association between AVCS and long-term mortality in a large TAVR patient sample. This study highlights the potential value of AVCS in preprocedural risk stratification, specifically among women undergoing TAVR. Additional studies are needed to validate this finding.

Abstract Introduction Doxorubicin is an anthracycline used as a chemotherapeutic drug for the treatment of a wide range of adult and pediatric cancers. Doxorubicin is associated with an increased risk of cardiomyopathy and heart failure with up to 10% of patients developing cardiac complications. A GWAS conducted of 1,191 patients from the N9831 clinical trial identified that cardiac gene expression and genetic variants of TRPC6 were associated with a decline in left ventricular ejection fraction (LVEF) (p=0.005 and p=1.6x10–6, respectively). TRPC6 is a non-selective cation channel expressed in heart and vascular tissue. TRPC6 participates in the pathogenesis of cardiac hypertrophy as a pathological response to chronic mechanical stress. Chronic activation has been found to promote cardiac fibrosis leading to heart failure. Purpose TRPC6 variants could be associated with increased risk of doxorubicin-induced cardiotoxicity. Data/tests to determine which patients may progress to cardiomyopathy and heart failure are currently lacking and there are no targeted treatments to prevent cardiomyopathy in these patients. Methods In preliminary in vivo data, B6.129 wild-type mice or TRPC6 knockout mice were treated with either 6x intraperitoneal saline or 4mg/kg doxorubicin injections (cumulative dose of 24mg/kg). Results We found doxorubicin increased cardiac vacuolation (male, p≤0.001 and female, p≤0.05) in WT mice compared to controls. Higher HW/BW ratio was observed in male TRPC6 knock out mice compared to wild-type mice when both were treated with doxorubicin (males, p=0.005 and females, p=0.19). Additionally, we found that doxorubicin-induced cardiac injury was significantly reduced in TRPC6 knock-out mice compared to wild-type mice based on reduced vacuolation (p=0.0004 males, p=0.03 females), with the effect being greater in male mice than female mice. Furthermore, a significant decrease in stroke volume (p=0.007), diastolic volume (p=0.01) and cardiac output (p=0.004) in wild-type male mice treated with doxorubicin compared to control and TRPC6 knock-out mice. Our in vitro preliminary data show that inhibition of TRPC6 using the TRPC6 inhibitor GsMTx-4 in human iPSC-derived cardiomyocytes significantly reduced doxorubicin-induced apoptosis (p&lt;0.0001). Further we treated male mice with the TRPC6 inhibitor, GsMTx4, and found that they had less global longitudinal cardiac strain (p=0.04) and higher ejection fraction (p=0.01) compared to mice who were only treated with doxorubicin. Histologically we found that mice given the TRPC6 inhibitor had less fibrosis as measured by Trichrome stained heart sections (p=0.004) which could account for improvements in cardiac function. Conclusion TRPC6 could be a novel therapeutic target in the prevention of chemotherapy-induced cardiomyopathy and heart failure. Additionally genetic mapping of TRCP6 functional variants may provide a new screening tool to determine increased risk of developing heart failure. Funding Acknowledgement Type of funding sources: Private hospital(s). Main funding source(s): Mayo Clinic

Background: Immunocompromised (IC) patients are at greater risk from cardiac surgery. Transcatheter aortic valve replacement (TAVR) may be more preferable for treating severe aortic stenosis (AS), though data regarding outcomes of IC patients are limited. Methods: We reviewed TAVR procedures performed at our institution from 1/2015-12/2019.We defined IC as either active malignancy receiving oncologic treatment or post organ transplant on immunosuppression, HIV, chronic steroid use (>5mg/day), or autoimmune disorder. Survival probability was estimated using the Kaplan-Meier (KM) method. Cox regression was used to evaluate the association of IC with survival. Results: Of 173 patients who underwent TAVR, 56 (32%) were IC: 30 (54%) had active malignancy undergoing active treatment, 19 (34%) were IC without malignancy, and 7 (13%) had both. Among the 19 IC patients without malignancy, 4 were post organ transplant, 3 were taking chronic steroids, 2 had autoimmune disorder, 1 had HIV, and 10 had ≥2 combination of the above. IC patients, as compared to non-IC patients, had similar baseline demographics and STS risk score (median 4.3 vs. 4.4), respectively. There were 37 deaths (16 IC and 21 non-IC) over a median follow up of 1.4 years (IQR 1.0-2.0 years). 1-year survival after TAVR was 84.5% for IC patients and 89.0% for non-IC patients (log rank p = 0.51). After adjusting for age and sex, an association between IC and survival was observed but not found to be statistically significant (adjusted HR, 1.55; 95% CI, 0.80-3.00). Conclusions: IC patients undergoing TAVR have similar baseline characteristics as non-IC patients with a trend towards worse survival. Longer term follow-up may help clarify the impact of IC status on survival after TAVR.

A 61-year-old male presented for an annual exam and received a transthoracic echocardiogram (TTE) which revealed a mobile mass arising from a subaortic membrane. Further investigations with a transesophageal echocardiogram (TEE) and cardiac computerized tomography angiography (CTA) confirmed the presence of a mobile 9 mm×3 mm mass on a subaortic membrane. Cardiothoracic surgery was performed with an open operation removing the mass and subaortic membrane. Upon visual inspection, the mass was likened to a sea anemone and immunohistochemical staining performed pathologically confirmed the diagnosis of cardiac papillary fibroelastoma. This case represents the first reported example of a cardiac papillary fibroelastoma (PFE) arising from a subaortic membrane. Although PFEs are benign cardiac tumors, proper identification and consideration for excision of these lesions may be indicated to prevent thromboembolic complications.

AbstractBackgroundSevere primary graft dysfunction (PGD) is the leading cause of early death after heart transplant.AimTo examine the outcomes of heart transplant recipients who received venoarterial extracorporeal membrane oxygenation (VA‐ECMO) for severe PGD.MethodsWe reviewed electronic health records of adult patients who underwent heart transplant from November 2005 through June 2015. We defined severe PGD according to International Society for Heart and Lung Transplantation consensus statements.ResultsOf 1030 heart transplant patients, 31 (3%) had severe PGD and required VA‐ECMO. The mean (range) age was 59 (43‐69) years. Fifteen patients (48%) underwent prior sternotomy and 10 (32%) received a left ventricular assist device as a bridge to transplant. Severe PGD manifested as failure to wean from cardiopulmonary bypass in 20 patients (65%) and as severe hemodynamic instability in the immediate postoperative period in 10 (32%), including cardiac arrest in 3 (10%). Twenty‐five patients (81%) were successfully weaned from VA‐ECMO, and 19 (61%) were discharged; the other 12 (39%) died.ConclusionsAlthough VA‐ECMO is a common method for providing mechanical circulatory support to patients with PGD, multicenter studies are needed to assess factors associated with successful outcomes and improved survival of these patients.