Immunosuppressive Therapy of Biopsy-Proven, Virus-Negative, Autoimmune/Immune-Mediated Myocarditis-Focus on Azathioprine: A Review of Existing Evidence and Future Perspectives.

The use of immunosuppressive therapy (IT) in biopsy-proven, autoimmune/immune-mediated (AI), virus-negative myocarditis has become the standard of care. In particular, according to recent guidelines, azathioprine (AZA), in association with steroids, is a cornerstone of first-line therapy regimens. IT may have a crucial impact on the natural history of AI myocarditis, preventing its progression to end-stage heart failure, cardiovascular death, or heart transplantation, provided that strict appropriateness and safety criteria are observed. In particular, AZA treatment for AI virus-negative myocarditis requires the consideration of some crucial aspects regarding its pharmacokinetics and pharmacodynamics, as well as a high index of suspicion to detect its overt and/or subclinical side effects. Importantly, besides a tight teamwork with a clinical immunologist/immuno-rheumatologist, before starting IT, it is also necessary to carry out a careful "safety check-list" in order to rule out possible contraindications to IT and minimize patient's risk. The aim of this review is to describe the pharmacological properties of AZA, as well as to discuss practical aspects of its clinical use, in the light of existing evidence, with particular regard to the new field of cardioimmunology.

Protamine sulfate during transcatheter aortic valve implantation (PS TAVI) - a single-center, single-blind, randomized placebo-controlled trial.

BACKGROUND: Bleeding complications after transcatheter aortic valve implantation (TAVI) negatively affect the post-procedural prognosis. Routine use of protamine sulfate (PS) to reverse unfractionated heparin after TAVI was never assessed in a randomized controlled trial. AIMS: The aim of this study was to assess the impact of PS on bleeding complications after TAVI. METHODS: Between December 2016 and July 2020 311 patients qualified to TAVI in one academic center were screened. Patients that met the inclusion criteria were randomized to either PS or normal saline administration at the moment of optimal valve deployment. Baseline, procedural, and follow-up data for up to 30 days were collected and analyzed. The primary endpoint (PE) was a composite of life-threatening and major bleeding according to Valve Academic Research Consortium within 48 hours after the procedure. RESULTS: Overall, 100 patients (48 males, median age 82 years) met the inclusion criteria and were included in the study. Forty-seven subjects (47%) were randomized to PS. The primary endpoint occurred in 29% of the study population. Despite numerically lower rates of PE in patients randomized to PS, a statistical significance was not reached (21% in the PS group and 36% in the placebo group; odds ratio [OR], 0.48; 95% confidence intervals [CI] 0.2-1.2; P = 0.11). There were no significant differences in secondary endpoints. CONCLUSIONS: Routine protamine sulfate administration did not significantly decrease the rate of major and life-threatening bleeding complications after TAVI. Larger studies are required to assess the impact of routine PS use.

Cardiac Arrhythmias in Muscular Dystrophies Associated with Emerinopathy and Laminopathy: A Cohort Study.

INTRODUCTION: Cardiac involvement in patients with muscular dystrophy associated with Lamin A/C mutations (LMNA) is characterized by atrioventricular conduction abnormalities and life-threatening cardiac arrhythmias. Little is known about cardiac involvement in patients with emerin mutation (EMD). The aim of our study was to describe and compare the prevalence and time distribution of cardiac arrhythmias at extended follow-up. PATIENTS AND METHODS: 45 consecutive patients affected by muscular dystrophy associated to laminopathy or emerinopathy were examined. All patients underwent clinical evaluation, 12-lead surface electrocardiogram (ECG), 24 h electrocardiographic monitoring, and cardiac implanted device interrogation. RESULTS: At the end of 11 (5.0-16.6) years of follow-up, 89% of the patients showed cardiac arrhythmias. The most prevalent was atrial standstill (AS) (31%), followed by atrial fibrillation/flutter (AF/Afl) (29%) and ventricular tachycardia (22%). EMD patients presented more frequently AF/AFl compared to LMNA (50% vs. 20%, p = 0.06). Half of the EMD patients presented with AS, whilst there was no occurrence of such in the LMNA (p = 0.001). Ventricular arrhythmias were found in 60% of patients with laminopathy compared to 3% in patients with emerinopathy (p < 0.001). The age of AVB occurrence was higher in the LMNA group (32.8 +/- 10.6 vs. 25.1 +/- 9.1, p = 0.03). CONCLUSIONS: Atrial arrhythmias are common findings in patients with muscular dystrophy associated with EMD/LMNA mutations; however, they occurred earlier in EMD patients. Ventricular arrhythmias were very common (60%) in LMNA and occurred definitely earlier compared to the EMD group.

Echocardiographic Features of Cardiomyopathy in Emery-Dreifuss Muscular Dystrophy.

BACKGROUND: Emery-Dreifuss muscular dystrophy (EDMD) is a very rare type of muscular dystrophy characterized by musculoskeletal abnormalities accompanied by cardiac defects. Two most common genetic subtypes are EDMD1 due to EMD and EDMD2 caused by LMNA gene mutations. The aim of the study was to characterize and compare the cardiac morphology and function in the two main genetic subgroups of EDMD with the use of echocardiography. METHODS: 41 patients with EDMD (29 EDMD1 and 12 EDMD2) as well as 25 healthy controls were enrolled in our study. Transthoracic echo with the use of a prescribed protocol was performed. RESULTS: Highly statistically significant differences with regard to left ventricle (LV) volumes between the EDMD and the control group were found. 51% of EDMD patients had an enlarged left atrium and as many as 71% had an enlarged right atrium. The LV ejection fraction (LVEF) was significantly lower in EDMD patients than in the control group which corresponded also with a lower systolic velocity of the mitral annulus. 43% of EDMD patients had LVEF below the normal limit. Diastolic dysfunction was detected in 17% of EDMD patients. There were no significant differences between the two types of EDMD in terms of diameters and volumes of any chamber, as well as the systolic function of both left and right ventricles. CONCLUSIONS: A significant number of EDMD patients present LV dilatation and different degrees of systolic dysfunction. Dilatation of the atria dominates over ventricle dilatation. We did not present any significant differences between EDMD1 and EDMD2 in terms of the morphology and the function of the heart.

Use of protamine sulfate during transfemoral transcatheter aortic valve implantation - a preliminary assessment of administration rate and impact on complications.

INTRODUCTION: Bleeding complications after transcatheter aortic valve implantation (TAVI) are an important issue and negatively affect survival. The rate and impact of protamine sulfate (PS) administration on bleeding complications after TAVI remain unclear. AIM: To assess the impact of PS on bleeding complications after TAVI. MATERIAL AND METHODS: Between March 2010 and November 2016 two hundred fifty-eight patients qualified for TAVI in one academic center were screened. Baseline, procedural and follow-up data up to 30 days were collected and analyzed. The primary endpoint (PE) was major bleeding according to the Valve Academic Research Consortium up to 48 h after the procedure. RESULTS: Overall, 186 patients (96 females, mean age: 80 years) met the inclusion criteria. Thirty-nine (21%) subjects received PS. PE occurred in 24.7% of the study population. There were no significant differences in terms of the PE rate between the groups (25.6% in the PS group and 24.7% in the remaining cohort, p = 0.9, odds ratio (OR) = 1.05, confidence interval (CI): 0.47-2.4, p = 0.9). Multivariate analysis identified female gender (OR = 2.2, CI: 1.08-4.4, p = 0.03) as an independent predictor of PE occurrence. Similarly, female gender (OR = 2, CI: 1.06-3.84, p = 0.03) as well as general anesthesia (GA, OR = 2.23, CI: 1.13-4.63, p = 0.02) and dose of unfractionated heparin per kilogram (UFH/kg, OR = 1.02, CI: 1-1.03 per 1 IU increment, p = 0.02) predicted the occurrence of a composite of major and minor bleeding. CONCLUSIONS: In this analysis, PS administration did not decrease the PE rate. Female gender predicted PE occurrence. Randomized, placebo-controlled trials are required to accurately assess the impact of PS.