Association of early electrical changes with cardiovascular outcomes in immune checkpoint inhibitor myocarditis.

BACKGROUND: Immune-checkpoint inhibitor-associated myocarditis (ICI-myocarditis) often presents with arrhythmias, but the prognostic value of early electrocardiogram findings is unclear. Although ICI-myocarditis and acute cellular rejection (ACR) following cardiac transplantation use similar treatment strategies, differences in arrhythmia burden are unknown. OBJECTIVE: To evaluate the association of electrocardiogram findings in ICI-myocarditis with myocarditis-related mortality and life-threatening arrhythmia. METHODS: A total of 125 cases of ICI-myocarditis were identified retrospectively across 49 hospitals worldwide; 50 cases of grade 2R or 3R ACR were included as comparators. Two cardiologists blinded to clinical data interpreted electrocardiograms. Associations between electrocardiogram features, myocarditis-related mortality and the composite of myocarditis-related mortality and life-threatening arrhythmias were examined. Adjusted hazard ratios (aHRs) were calculated. RESULTS: The cohort had 78 (62.4%) men; median (interquartile range) age was 67 (58-76) years. At 30 days, myocarditis-related mortality was 20/124 (16.1%), and 28/124 (22.6%) met the composite endpoint. Patients who developed complete heart block (aHR by subdistribution hazards model [aHR(sh)] 3.29, 95% confidence interval [CI] 1.24-8.68; P=0.02) or life-threatening cardiac arrhythmias (aHR(sh) 6.82, 95% CI: 2.87-16.21; P<0.001) had a higher risk of myocarditis-related mortality. Pathological Q waves (aHR(sh) 3.40, 95% CI: 1.38-8.33; P=0.008), low QRS voltage (aHR(sh) 6.05, 95% CI: 2.10-17.39; P<0.001) and Sokolow-Lyon index (aHR(sh)/mV 0.54, 95% CI: 0.30-0.97; P=0.04) on admission electrocardiogram were also associated with increased risk of myocarditis-related mortality. These associations were mirrored in the composite outcome analysis. Compared with ACR, ICI-myocarditis had a higher incidence of life-threatening cardiac arrhythmias (15/125 [12.0%] vs 1/50 [2%]; P=0.04) and third-degree heart block (19/125 [15.2%] vs 0/50 [0%]; P=0.004). CONCLUSIONS: Electrocardiograms in ICI-myocarditis with ventricular tachycardias, heart block, low-voltage and pathological Q waves were associated with myocarditis-related mortality and life-threating arrhythmia. Arrhythmia burden in ICI-myocarditis exceeds that of ACR after heart transplant.

Relapsing polychondritis associated with heart block.

OBJECTIVE: The present article aims at describing a rare case of an RP patient who evolved with heart block and was successfully treated with corticoid pulse therapy, without the need for pacemaker insertion. PATIENTS AND METHODS: A systematic research on relapsing polychondritis (RP) and heart block (HB) published in PubMed/MEDLINE, Web of Sciences, LILACS, and Scielo from 1966 to August 2020 was performed. RESULTS: It was found 10 studies on RP associated with HB, and we added a case. Most were male (7/10) with ages 30 to 66 years old. RP disease duration was 1 week-6 years. In most cases (7/10), the RP was active when the HB occurred. A complete HB was observed in 4/7, followed by type II degree block in 3/7, and one patient had a sinus node dysfunction. Most patients received glucocorticoids. A pacemaker was inserted in 4/9 cases. Good outcome was observed in 3/9 patients and mortality in 2/10. CONCLUSIONS: We report the first case of an RP patient who had a heart block and was successfully treated with methylprednisolone pulse therapy. The authors suggest that in these RP cases, an attempt with a glucocorticoid pulse therapy may be offered to treat the heart block and prevent the insertion of a pacemaker.

Hydroxychloroquine to Prevent Recurrent Congenital Heart Block in Fetuses of Anti-SSA/Ro-Positive Mothers.

BACKGROUND: Experimental and clinical evidence support the role of macrophage Toll-like receptor signaling in maternal anti-SSA/Ro-mediated congenital heart block (CHB). OBJECTIVES: Hydroxychloroquine (HCQ), an orally administered Toll-like receptor antagonist widely used in lupus including during pregnancy, was evaluated for efficacy in reducing the historical 18% recurrence rate of CHB. METHODS: This multicenter, open-label, single-arm, 2-stage clinical trial was designed using Simon's optimal approach. Anti-SSA/Ro-positive mothers with a previous pregnancy complicated by CHB were recruited (n = 19 Stage 1; n = 35 Stage 2). Patients received 400 mg daily of HCQ prior to completion of gestational week 10, which was maintained through pregnancy. The primary outcome was 2° or 3° CHB any time during pregnancy, and secondary outcomes included isolated endocardial fibroelastosis, 1° CHB at birth and skin rash. RESULTS: By intention-to-treat (ITT) analysis, 4 of 54 evaluable pregnancies resulted in a primary outcome (7.4%; 90% confidence interval: 3.4% to 15.9%). Because 9 mothers took potentially confounding medications (fluorinated glucocorticoids and/or intravenous immunoglobulin) after enrollment but prior to a primary outcome, to evaluate HCQ alone, 9 additional mothers were recruited and followed the identical protocol. In the per-protocol analysis restricted to pregnancies exposed to HCQ alone, 4 of 54 (7.4%) fetuses developed a primary outcome as in the ITT. Secondary outcomes included mild endocardial fibroelastosis (n = 1) and cutaneous neonatal lupus (n = 4). CONCLUSIONS: These prospective data support that HCQ significantly reduces the recurrence of CHB below the historical rate by >50%, suggesting that this drug should be prescribed for secondary prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies. (Preventive Approach to Congenital Heart Block With Hydroxychloroquine [PATCH]; NCT01379573).

A case of bidirectional conduction block within the superior vena cava induced by cryoballoon pulmonary vein isolation.

A 53-year-old male underwent a pulmonary vein isolation (PVI) of atrial fibrillation (AF) with a second-generation cryoballoon (CB). Although the patient maintained sinus rhythm after the PVI, a superior vena cava (SVC) fibrillation was recorded by a circular-multipolar-electrode catheter positioned inside the SVC that suggested conduction block between the right atrium (RA)-SVC connection. An adenosine triphosphate intravenous injection induced a dormant reconnection of the SVC myocardial sleeve and converted sinus rhythm to an AF rhythm. This case demonstrated that a CB application for the isolation of a right superior pulmonary vein could induce an electrical conduction block between the RA-SVC connection.

Two case reports of neonatal autoantibody-associated congenital heart block.

RATIONALE: Neonatal lupus erythematosus (NLE) is an infrequent disease caused by transplacental maternal autoantibodies. The most common effects of NLE include cutaneous involvement and congenital heart block (CHB), although it might involve multiple organs, such as the liver, lungs, blood, and nervous or digestive systems. Izmirly PM1 and Tonello et al recently reported cutaneous manifestations of neonatal lupus and risk of subsequent CHB. The most serious complication of NLE is complete atrioventricular (AV) block. PATIENT CONCERNS: We experienced 2 cases of NLE that were diagnosed in the past year in our Neonatal Intensive Care Unit. These cases showed 2 different clinical spectrums (CHB, multisystemic effects). One case was a 32-week pregnant woman with combined liver damage and fever, and her fetus was premature due to bradycardia and pericardial effusion. The second case was a young pregnant woman who had systemic lupus erythematosus for 2 years and had been taking methylprednisolone and hydroxychloroquine for a long time since her illness. When prenatal testing at 28 weeks of pregnancy showed that the fetus had CHB, the mother began taking dexamethasone. DIAGNOSIS: The first case was diagnosed as NLE with CHB after birth, while the second was diagnosed as NLE with CHB, ductus arteriosus, and atrial septal defect when she was born at 34 weeks. INTERVENTIONS: Both of 2 cases were treated with steroids, intravenous immunoglobulin, and a diuretic. But the second case was treated with isoprenaline in addition to the above. OUTCOMES: Both of the infants was followed up and found to be clinically normal. During the clinic follow-up of the first case, the 8-month-old infant was still asymptomatic with normal growth and development. Her heart rate fluctuated from 40 to 90 beats/minute. LESSONS: Autoimmune CHB is a severe, potentially life-threatening disorder associated with passive transfer of maternal anti-Sjogren's syndrome A/Ro and anti-Sjogren's syndrome B/La autoantibodies. Mothers who are positive for these autoantibodies are recommended to have serial echocardiography and obstetric ultrasonography from the early second trimester. Newborns should be delivered at an early stage of gestation if there is evidence of pericardial effusion, ascites, increasing ventricular ectopy, reduced ventricular shortening fraction, or AV valve regurgitation. Aggressive medical management after birth should be coupled with pacemaker implantation in infants who do not respond to medical therapies alone.

Intra- and interatrial conduction abnormalities: hemodynamic and arrhythmic significance.

Alterations of normal intra- and interatrial conduction are a common outcome of multiple cardiovascular conditions. They arise most commonly in the context of advanced age, cardiovascular risk factors, organic heart disease, atrial fibrosis, and left atrial enlargement. Interatrial block (IAB), the most frequent and extensively studied atrial conduction disorder, affects up to 20% of the general primary care population. IAB can be partial (P wave duration ≥ 120 ms on any of the 12 ECG leads) or advanced (P wave ≥ 120 ms and biphasic morphology (positive-negative) in inferior leads). Advanced IAB is an independent risk factor for supraventricular tachyarrhythmias and embolic stroke in a variety of clinical settings. Advanced IAB is a cause of left atrial electromechanical dysfunction and left atrioventricular dyssynchrony and has been associated with left ventricular diastolic dysfunction. P wave duration is associated with cardiovascular and all-cause mortality in the general population. Atrial conduction abnormalities should be identified as markers of atrial remodeling, prognostic indicators, and, in the case of advanced IAB, a true arrhythmologic syndrome. IAB and other P wave abnormalities should prompt the search for associated conditions, the treatment of which may partially reverse atrial remodeling or prevent it if administered upstream. Future studies will help define the role of preventive therapeutic interventions in high-risk patients, including antiarrhythmic drug therapy and oral anticoagulation. Implications for the treatment of heart failure and for pacing should also be further investigated.

Resolution of sinus bradycardia, high-grade heart block, and left ventricular systolic dysfunction with rituximab therapy in Henoch-Schonlein purpura.

Henoch-Schonlein purpura (HSP) is a rare, typically self-limited, multi-organ vasculitis. Cardiac involvement with HSP carries high morbidity and mortality, thus requiring early aggressive immunosuppressive therapy. We report a case of HSP complicated with acute systolic left ventricular (LV) dysfunction, symptomatic sinus bradycardia and high-grade atrio-ventricular (AV) heart block. Cyclophosphamide, a commonly used agent in HSP, was contraindicated due to the patient's presentation with acute renal failure. Treatment with monoclonal antibody rituximab and corticosteroids was initiated with an improvement in and resolution of LV systolic dysfunction, sinus bradycardia and AV block. We believe this is the first published report on rituximab treatment in HSP with cardiac involvement manifesting with severe LV systolic dysfunction, sinus bradycardia and high-grade AV block.

Transient receptor potential melastatin 4 cation channel in pediatric heart block.

OBJECTIVE: Progressive cardiac conduction disease (PCCD) is a common pediatric heart conduction disorder. It is an autosomal inheritance of rare mutations, which leads to familial cases of PCCD. In these cases, the His-Purkinje system's conductive capacity is progressively deranged, involving either right or left bundle branch block. Also, QRS complexes display widening is an important characteristic that culminates in complete AV block, syncope, and sudden death. Mutations in TRPM4 gene that encodes for transient receptor potential melastatin 4 have recently been reported to cause familial cases of PCCD and heart block. TRPM4 conducts a Ca2+-activated non-selective monovalent cationic current leading to a negative plasma membrane potential. TRPM4 channels let Na+ ion influx, causing membrane depolarization, whereas, at positive membrane potentials, TRPM4 channels repolarize the membrane by facilitating K+ ion efflux from the cell. TRPM4 protein contains many regulatory motifs that confer voltage dependence, ATP/ADP sensitivity, and Ca2+ responsiveness. Mutational studies revealed the significance of the two-calmodulin binding sites at the N-terminus of for Ca2+ dependent activation of this channel. Mutations that reduce deSUMOylation increase the steady-state levels of active TRPM4 channels on the membrane without alteration of its sensitivity to Ca2+ or ATP or its voltage dependence of activation. Increased TRPM4 function interferes with cardiac conduction and eventually contributes to heart block. Both gain and loss of function mutations of TRPM4 are implicated in the cardiac block. Currently, the major therapeutic management of cardiac block due to TRPM4 mutations is implantation of a pacemaker to reinstate normal current propagation through AV node.

No histologic evidence of foetal cardiotoxicity following exposure to maternal hydroxychloroquine.

It is currently recommended that hydroxychloroquine (HCQ) be maintained during pregnancy in patients with systemic lupus erythematosus. Recent data suggest that this Toll-like receptor inhibitor may also reduce the recurrence rate of anti-SSA/Ro associated congenital heart block (CHB). This case report describes a unique situation in which a CHB-afflicted, HCQ-exposed pregnancy was electively terminated. The heart did not reveal any characteristic features of cardiotoxicity, providing further evidence supporting the safety of foetal exposure to HCQ.

Serial echocardiography for immune-mediated heart disease in the fetus: results of a risk-based prospective surveillance strategy.

OBJECTIVE: Mothers carrying anti-Ro antibodies are frequently referred for weekly echocardiograms to early detect and treat antibody-mediated fetal heart disease. We tested a surveillance strategy based on anti-Ro antibody titers. METHODS: From 2009 to 2014, 232 pregnancies were referred for maternal anti-Ro antibodies. At the baseline echocardiogram, anti-Ro titers were measured by enzyme-linked immunosorbent essay and results categorized as negative (<8 U/mL; n = 43; excluded), low-moderate positive (8-49 U/mL; n = 62; group 1) or high positive (50 - >100 U/mL; n = 127; group 2). Serial echocardiograms to ≥24 weeks were only recommended for group 2 mothers. RESULTS: Group 1 patients underwent significantly less fetal echocardiograms when compared with group 2 mothers (median 2 vs. 4; p < 0.001). Isolated endocardial fibroelastosis (n = 1) and incomplete (n = 4) or complete (n = 4) heart block were diagnosed in 9 (8%) pregnancies with anti-Ro titers >100 U/mL but none with lower titers (odds ratio 17.78; p = 0.004). Incomplete block and endocardial fibroelastosis regressed with transplacental corticosteroid and immune globulin therapy. CONCLUSIONS: Limiting serial fetal echocardiograms to women with high anti-Ro antibody levels is safe and more cost effective. While numbers of echocardiograms were significantly reduced in referrals with anti-Ro titers <50 U/mL, reversible abnormalities with prenatal treatment were detected by serial echocardiography in group 2 patients. © 2017 John Wiley & Sons, Ltd.

Calidad de la recuperación posquirúrgica tras cirugía de mama. Anestesia general combinada con bloqueo paravertebral versus bloqueo del espacio serrato-intercostal / Quality of postoperative recovery after breast surgery. General anaesthesia combined with paravertebral versus serratus-intercostal block

Introducción. La cuantificación de la calidad de la recuperación posquirúrgica destaca entre los indicadores de calidad utilizados en clínica. Ello es más importante aún tras cirugía oncológica. Nuestro objetivo fue evaluar la calidad de la recuperación tras cirugía no reconstructiva de mama tras anestesia general combinada con bloqueo paravertebral versus bloqueo del espacio serrato-intercostal en el postoperatorio inmediato y tardío. Material y métodos. Estudio observacional prospectivo en 60 pacientes programadas para cirugía no reconstructiva de mama en un periodo de 6 meses bajo anestesia combinada general y bloqueo paravertebral (25 pacientes) o bloqueo del espacio serrato-intercostal (35 pacientes). La calidad de la recuperación postanestésica se midió con la escala Postoperative Quality Recovery Scale, valorando los dominios fisiológico, nociceptivo, emocional, autonomía, cognitivo y estado general en diferentes momentos: basal (previo a cirugía), 15min tras finalizar la intervención, al alta hospitalaria y al mes postintervención. Resultados. Se consiguió una recuperación total del 95,93% en el postoperatorio inmediato (15 min unidad de recuperación postoperatoria [URPA]), del 99,07% al alta y del 99,25% al mes de la intervención. No se encontraron diferencias significativas entre ambos grupos ni en la puntuación total ni en las diversas áreas medidas por la escala. Conclusiones. Con la técnica descrita se ha objetivado una alta puntuación de recuperación con la Postoperative Quality Recovery Scale, que posibilitaría el alta en el postoperatorio inmediato y la vuelta precoz a la vida activa habitual. En ambos grupos se observó un ahorro de opioides y una recuperación excelente de todos los dominios evaluados, sin diferencias significativas (AU)

Introduction. The quality of postoperative recovery is one of the most important among all the quality indicators used in clinical situations. This is even more important after cancer surgery. Our aim was to evaluate this after non-reconstructive breast surgery under general anesthesia and paravertebral blockade or serratus-intercostal plane blockade, in the early and late post-operative period. Material and methods. A prospective observational study was conducted on 60 patients (25 paravertebral blockade group and 35 serratus-intercostal plane blockade group) scheduled for non-reconstructive breast surgery during a 6 month period. Every patient received general anaesthesia and were randomised to receive either paravertebral blockade or serratus-intercostal plane blockade. The quality of post-anaesthetic recovery was quantified by Postoperative Quality Recovery Scale, which is used to assess physiological, nociceptive, emotional, autonomy, cognitive and general state domains at different times: baseline (before surgery), 15min after the end of surgery, at discharge to home, and one month after surgery. Results. A total recovery of 95.93% was achieved in the early postoperative period (15min PACU), 99.07% at discharge to home, and 99.25% at one month after the intervention. No significant differences were found between groups in total score or in each evaluated area. Conclusions. A progressive improvement was observed in the scores assessed with the Postoperative Quality Recovery Scale, reaching values that would allow the discharge to home and early return to usual active life from the immediate postoperative period, with no significant differences between the 2 analgesic techniques. Savings in opioid use and the excellent recovery were observed in all measured domains observed (AU)

Assessment of fluorinated steroids to avert progression and mortality in anti-SSA/Ro-associated cardiac injury limited to the fetal conduction system.

OBJECTIVES: Extension of disease beyond the atrioventricular (AV) node is associated with increased mortality in cardiac neonatal lupus (NL). Treatment of isolated heart block with fluorinated steroids to prevent disease progression has been considered but published data are limited and discordant regarding efficacy. This study evaluated whether fluorinated steroids given to manage isolated advanced block prevented development of disease beyond the AV node and conferred a survival benefit. METHODS: In this retrospective study of cases enrolled in the Research Registry for NL, inclusion was restricted to anti-SSA/Ro-exposed cases presenting with isolated advanced heart block in utero who either received fluorinated steroids within 1 week of detection (N=71) or no treatment (N=85). Outcomes evaluated were: development of endocardial fibroelastosis, dilated cardiomyopathy and/or hydrops fetalis; mortality and pacemaker implantation. RESULTS: In Cox proportional hazards regression analyses, fluorinated steroids did not significantly prevent development of disease beyond the AV node (adjusted HR=0.90; 95% CI 0.43 to 1.85; p=0.77), reduce mortality (HR=1.63; 95% CI 0.43 to 6.14; p=0.47) or forestall/prevent pacemaker implantation (HR=0.87; 95% CI 0.57 to 1.33; p=0.53). No risk factors for development of disease beyond the AV node were identified. CONCLUSIONS: These data do not provide evidence to support the use of fluorinated steroids to prevent disease progression or death in cases presenting with isolated heart block.

Fetal and Neonatal Arrhythmias.

Cardiac arrhythmias are an important aspect of fetal and neonatal medicine. Premature complexes of atrial or ventricular origin are the main cause of an irregular heart rhythm. The finding is typically unrelated to an identifiable cause and no treatment is required. Tachyarrhythmia most commonly relates to supraventricular reentrant tachycardia, atrial flutter, and sinus tachycardia. Several antiarrhythmic agents are available for the perinatal treatment of tachyarrhythmias. Enduring bradycardia may result from sinus node dysfunction, complete heart block and nonconducted atrial bigeminy as the main arrhythmia mechanisms. The management and outcome of bradycardia depend on the underlying mechanism.

G protein-gated IKACh channels as therapeutic targets for treatment of sick sinus syndrome and heart block.

Dysfunction of pacemaker activity in the sinoatrial node (SAN) underlies "sick sinus" syndrome (SSS), a common clinical condition characterized by abnormally low heart rate (bradycardia). If untreated, SSS carries potentially life-threatening symptoms, such as syncope and end-stage organ hypoperfusion. The only currently available therapy for SSS consists of electronic pacemaker implantation. Mice lacking L-type Cav1.3 Ca(2+) channels (Cav1.3(-/-)) recapitulate several symptoms of SSS in humans, including bradycardia and atrioventricular (AV) dysfunction (heart block). Here, we tested whether genetic ablation or pharmacological inhibition of the muscarinic-gated K(+) channel (IKACh) could rescue SSS and heart block in Cav1.3(-/-) mice. We found that genetic inactivation of IKACh abolished SSS symptoms in Cav1.3(-/-) mice without reducing the relative degree of heart rate regulation. Rescuing of SAN and AV dysfunction could be obtained also by pharmacological inhibition of IKACh either in Cav1.3(-/-) mice or following selective inhibition of Cav1.3-mediated L-type Ca(2+) (ICa,L) current in vivo. Ablation of IKACh prevented dysfunction of SAN pacemaker activity by allowing net inward current to flow during the diastolic depolarization phase under cholinergic activation. Our data suggest that patients affected by SSS and heart block may benefit from IKACh suppression achieved by gene therapy or selective pharmacological inhibition.

Congenital heart block related to maternal autoantibodies: descriptive analysis of a series of 18 cases from a single center.

The objective of this study was to describe the clinical and immunological characteristics of maternal autoimmune-mediated fetal congenital heart block (CHB) in a cohort of pregnant women from an autoimmune disease pregnancy clinic. This is a retrospective observational study of all women presenting with CHB in our autoimmune disease pregnancy clinic from January 1997 to December 2014. In addition, perinatal outcome is also described. Fourteen patients accounting for 18 fetuses with CHB were identified. The median age was 32.5 years (range, 22-40). Seven (50 %) patients had Sjögren's syndrome, and the remaining seven were asymptomatic carriers of autoantibodies. All patients had anti-Ro/SSA antibodies, and 11/13 (85 %) had anti-La/SSB antibodies. The median gestational age at the time of CHB was 22 weeks (range 18-28). Complete third degree CHB was detected in 12 (67 %). Seven cases of CHB were treated with dexamethasone, two with ritodrine, and one with the association of dexamethasone, ritodrine, and terbutaline. In 9 (50 %) cases that presented with, or developed, very poor prognosis factors, such as a ventricular rate below 50-55 bpm and/or the presence of fetal hydrops, parents opted for the termination of pregnancy, after dedicated counseling. Finally, there were nine newborns (seven males [78 %]) with median age at delivery of 37 weeks (range, 32-39). A definitive epicardial pacemaker was placed in six newborns, four of them within 2 weeks of life. CHB is a severe complication related to maternal anti-Ro/SSA and anti-La/SSB antibodies. Our results confirm previous data showing that therapy is ineffective, and most of the surviving patients will require neonatal pacemaker.