Background: Advances in radiotherapy for thoracic cancers have resulted in improvement of survival. However, radiation exposure to the heart can induce cardiotoxicity. No therapy is currently available to inhibit these untoward effects. We examined whether a small tetrapeptide, N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), can counteract radiation-induced cardiotoxicity by inhibiting macrophage-dependent inflammatory and fibrotic pathways.Methods and Results: After characterizing a rat model of cardiac irradiation with magnetic resonance imaging protocols, we examined the effects of Ac-SDKP in radiation-induced cardiomyopathy. We treated rats with Ac-SDKP for 18 weeks. We then compared myocardial contractile function and extracellular matrix by cardiac magnetic resonance imaging and the extent of inflammation, fibrosis, and Mac-2 (galectin-3) release by tissue analyses. Because Mac-2 is a crucial macrophage-derived mediator of fibrosis, we performed studies to determine Mac-2 synthesis by macrophages in response to radiation, and change in profibrotic responses byMac-2gene depleted cardiac fibroblasts after radiation. Cardiac irradiation diminished myocardial contractile velocities and enhanced extracellular matrix deposition. This was accompanied by macrophage infiltration, fibrosis, cardiomyocyte apoptosis, and cardiac Mac-2 expression. Ac-SDKP strongly inhibited these detrimental effects. Ac-SDKP migrated into the perinuclear cytoplasm of the macrophages and inhibited radiation-induced Mac-2 release. Cardiac fibroblasts lacking theMac-2gene showed reduced transforming growth factor β1, collagen I, and collagen III expression after radiation exposure.Conclusions: Our study identifies novel cardioprotective effects of Ac-SDKP in a model of cardiac irradiation. These protective effects are exerted by inhibiting inflammation, fibrosis, and reducing macrophage activation. This study shows a therapeutic potential of this endogenously released peptide to counteract radiation-induced cardiomyopathy.

Background: Cancer survivors with prior chest radiation therapy (C-XRT) frequently present with aortic stenosis (AS) as the first manifestation of radiation-induced heart disease. They are considered high-risk for surgical valve replacement. Transcatheter aortic valve replacement (TAVR) is as an attractive option for this patient population but the outcomes are not well established in major clinical trials. The authors performed a systemic review and meta-analysis of clinical studies for the outcomes after TAVR in cancer survivors with prior C-XRT. Methods: Online databases were searched from inception to April 2020 for studies evaluating the outcomes of TAVR in patients with and without C-XRT. We analyzed the pooled estimates (with their 95% confidence intervals) of the odds ratio (OR) for the all-cause mortality at 30-day and 1-year follow-ups, 4-point safety outcomes (stroke, major bleed, access-related vascular complications and need for a pacemaker), a 2-point efficacy outcome (mean aortic valve gradient and left ventricular ejection fraction) and worsening of congestive heart failure (CHF). Four studies were included following 2054 patients with and without prior C-XRT exposure (164 patients and 1890 patients respectively). Results: The C-XRT group had similar 30-day mortality compared to the control group (OR 1.29, 95% CI 0.64 to 2.58, p = 0.48). The 1-year mortality was higher in the C-XRT group (OR 1.97, CI 1.15 to 3.39, p = 0.01). Apart from higher congestive heart failure (CHF) exacerbation in the C-XRT group (OR 2.03, CI 1.36 to 3.04, p = 0.0006), TAVR resulted in similar safety and efficacy outcomes in both groups. Conclusion: TAVR in the C-XRT group has similar 30-day mortality, safety, and efficacy outcomes compared to the control group; however, they have higher 1-year mortality and CHF exacerbation. Including an oncologist to the cardiology team who considers cancer stage in the decision-making process and applying additional preoperative scores such as frailty indices may refine the risk assessment for these patients. The quality of analyzed data is modest, warranting randomized trials to assess the true benefits of TAVR in these patients.

Improved cancer survival in patients treated with thoracic ionizing radiation (XRT) has resulted in unanticipated surge of aortic stenosis. Transcatheter aortic valve replacement (TAVR) has revolutionized the management of severe aortic stenosis. However, long-term clinical outcomes in radiation-exposed cohorts undergoing TAVR are unknown. We compared the all-cause mortality and major adverse cardiac events (MACE) in patients with prior chest XRT (C-XRT) undergoing TAVR. This is an observational cohort study in subjects who underwent TAVR for symptomatic severe aortic stenosis from 2012 to 2017 in a tertiary care referral center. We examined the all-cause mortality and MACE using cox proportional hazard analysis to identify the clinical predictors of survival in the cohort of patients who had a history of prior C-XRT for malignancy. Of the 610 patients who underwent TAVR for symptomatic severe aortic stenosis, 75 had prior C-XRT. The majority of C-XRT patients had prior breast cancer (44%) followed by Hodgkin’s lymphoma (31%), with the median time from XRT to TAVR of 19.0 years. During a mean follow up of 17.1 months after TAVR, all-cause mortality was 17%. Those with prior C-XRT had higher all-cause mortality (XRT: 29%; non-XRT:15%, p < 0.01) and MACE (XRT: 57%; non-XRT: 27%, p < 0.001) after TAVR. Patients with prior XRT had a higher incidence of atrial fibrillation (XRT: 48%; non-XRT: 2.4%, p < 0.01) and high-grade heart block (XRT: 20%; non-XRT: 9.1%, p = 0.007) requiring pacemaker implant after TAVR. On multivariate cox proportional hazard analysis, prior XRT (HR: 2.07, p = 0.003), poor renal function (HR: 1.29, p < 0.001) and post-operative anemia requiring transfusion (HR: 1.16, p:0.001) were the strongest predictors of reduced survival. Cancer survivors with prior C- XRT have higher incidence of all-cause mortality and MACE after TAVR. Careful patient selection and follow-up strategies are needed to improve outcomes.

Background: Myocardial fibrosis is a common postmortem finding among individuals with Sudden Cardiac Death (SCD). Numerous in vivo and in vitro studies have shown that increased galectin-3 (gal3) expression into the myocardium is associated with higher incidence of fibrosis. Although elevated gal3 expression is linked with myocardial fibrosis, its role in predicting the risk of SCD is unknown. Methods: We reviewed the clinical datasets and post-mortem examination of 221 subjects who had died suddenly. We examined myocardial pathology including the extent of cardiac hypertrophy, fibrosis, and the degree of coronary atherosclerosis in these subjects. In a select group of SCD subjects, we studied myocardial gal3 and periostin expression using immunohistochemistry. To further examine if a higher level of circulating gal3 can be detected preceding sudden death, we measured serum gal3 in a porcine model of subtotal coronary artery ligation which shows an increased tendency to develop lethal cardiac arrhythmias, including ventricular tachycardia or fibrillation. Results: Of the total 1314 human subjects screened, 12.7% had SCD. Comparison of age-matched SCD with non-SCD subjects showed that SCD groups had excessive myocardial fibrosis involving both the left ventricular free wall and interventricular septum. In pigs with subtotal coronary artery ligation and SCD, we detected significantly elevated circulating gal3 levels approximately 10 days preceding the SCD event. Immunohistochemistry showed increased myocardial gal3 and periostin expression in pigs that died suddenly, compared to the controls. Conclusion: Our study shows that increased gal3 is associated with a higher risk of myocardial fibrosis and the risk of SCD. This supports the importance of larger translational studies to target gal3 to prevent cardiac fibrosis and attenuate the risk of SCD.