Routine ambulatory heart rhythm monitoring for detection of atrial arrhythmias in transthyretin cardiac amyloidosis.

BACKGROUND: Atrial fibrillation and flutter (AF/AFL) are common in transthyretin cardiac amyloidosis (ATTR-CM) which in turn is associated with higher risk of thromboembolism. Detecting AF/AFL may be especially important, but the role of routine ambulatory monitoring in ATTR-CM patients is unclear. OBJECTIVE: The objective is therefore to determine prevalence and outcomes of subclinical AF/AFL on routine ambulatory rhythm monitoring. METHODS: We report outcomes of an observational study of patients at our Amyloidosis Center with wild-type or variant ATTR-CM diagnosed between 2005 and 2019. Patients without known AF/AFL at baseline had ambulatory ECG monitoring (duration 2-30 days) every 6 months while those with cardiovascular implantable electronic devices (CIEDs) had device interrogations instead. RESULTS: Eighty-four patients with ATTR-CM (mean age 73.5 ± 9.7 years, 94% male) had mean follow-up 2.3 ± 1.9 years. Forty patients (48%) had AF/AFL before ATTR-CM diagnosis. In the remainder, 21 (48%) were subsequently diagnosed with AF/AFL: 10 (48%) based on symptoms, and 11 (52%) by monitoring. Anticoagulation (AC) was started in 9/11 (82%) patients with incidental AF/AFL. Among the entire cohort, stroke occurred in 9 patients (11%): 1 hemorrhagic and 8 ischemic (7 in patients with AF/AFL). No strokes occurred in patients on AC. CONCLUSION: Almost half of patients in our cohort had AF/AFL diagnosed prior to their ATTR-CM diagnosis. In the remainder, approximately half of AF/AFL diagnoses were established incidentally by routine monitoring, most of whom were promptly anticoagulated. Incidence of stroke was high overall, but no strokes occurred in anticoagulated patients. Optimal frequency and duration of monitoring needs further investigation.

Mode of death and outcomes of implantable cardioverter defibrillators in transthyretin amyloid cardiomyopathy.

INTRODUCTION: Transthyretin cardiac amyloidosis (ATTR-CM) may associate with sudden cardiac death. We report on the mode of death and outcomes with implantable cardioverter defibrillators (ICDs) in a cohort with ATTR-CM. METHODS: A single center observational cohort study of patients with ATTR-CM diagnosed between 2005 and 2019. ICD implant was at discretion of treating cardiologists. Medians are expressed with 25th,75th percentiles. RESULTS: Eighty-four patients with ATTR-CM (age 73.5 ± 9.7 years, 94% male, median follow-up 21.1 months (11.4-38.1). Nineteen patients (23%) underwent ICD implantation - 18 for primary and 1 for secondary prevention. In the primary prevention ICD group, 1 patient had 2 inappropriate shocks, 1 patient had appropriate ATP on 3 occasions. One patient (mixed ischemic cardiomyopathy and ATTR-CM) with secondary prevention ICD had 15 appropriate shocks in 3 episodes of VT storm. In patients without ICD, ambulatory monitoring review (14,764 h) did not reveal sustained ventricular arrhythmia. Excluding the one patient with secondary prevention ICD, 5 (28%) in the primary prevention ICD group and 22 (34%) in the non-ICD group died, p = 0.14. Mode of death did not vary between both groups. CONCLUSIONS: Patients with ATTR-CM and primary prevention ICD infrequently receive appropriate device therapy without differing in mode of death, which was mainly related to progressive heart failure, compared to those without ICD.

Management Strategies for Atrial Fibrillation and Flutter in Patients with Transthyretin Cardiac Amyloidosis.

Atrial fibrillation (AF) and flutter (AFL) frequently complicate transthyretin cardiac amyloidosis (ATTR-CM). Management poses challenges as rate control drugs are poorly tolerated and data addressing tolerability and efficacy of rhythm control is limited. We report outcomes of AF/AFL in ATTR-CM in a single center observational study of patients seen at our Amyloidosis Center with wild-type or hereditary ATTR-CM diagnosed between 2005-2019 including 84 patients (average age 74 ± 10 years, 94% male) with 27.6 ± 22.8 months follow-up. AF/AFL occurred in 61 patients (73%). Rapid ventricular response was common as was attempted rate control. However, discontinuation of rate control drugs was frequent (80%), often for adverse effects. Rhythm control was attempted in 64%, usually with cardioversion (DCCV) or ablation. Post-DCCV recurrence was common (91%) and time to recurrence was similar with or without anti-arrhythmic drugs (5.8 months (IQR 1.9-12.5) vs 6.2 months (IQR 1.9-12.5) p = 0.83). Ablation was performed in 23% with AFL (all for typical AFL) with 14% recurrence after mean of 60.9 months. Ablation for AF was performed in 12% with 86% recurrence after median of 6.2 months (IQR 5.6-12.3). Most patients (62%) with rhythm control had subjective improvement (≥1 NYHA class or resolved palpitations). In conclusion, AF/AFL was common in our cohort. Rate control was poorly tolerated and often abandoned. Rhythm control led to symptomatic improvement in a majority of cases, but durable success was limited. DCCV was modestly successful and not significantly improved with anti-arrhythmics. Ablation was successful with typical AFL but had limited success in AF.

Appropriate and inappropriate shocks in hypertrophic cardiomyopathy patients with subcutaneous implantable cardioverter-defibrillators: An international multicenter study.

BACKGROUND: Subcutaneous implantable cardioverter-defibrillators (S-ICDs) are attractive for preventing sudden cardiac death in hypertrophic cardiomyopathy (HCM) as they mitigate risks of transvenous leads in young patients. However, S-ICDs may be associated with increased inappropriate shock (IAS) in HCM patients. OBJECTIVE: The purpose of this study was to assess the incidence and predictors of appropriate shock and IAS in a contemporary HCM S-ICD cohort. METHODS: We collected electrocardiographic and clinical data from HCM patients who underwent S-ICD implantation at 4 centers. Etiologies of all S-ICD shocks were adjudicated. We used Firth penalized logistic regression to derive adjusted odds ratios (aORs) for predictors of IAS. RESULTS: Eighty-eight HCM patients received S-ICDs (81 for primary and 7 for secondary prevention) with a mean follow-up of 2.7 years. Five patients (5.7%) had 9 IAS episodes (3.8 IAS per 100 patient-years) most often because of sinus tachycardia and/or T-wave oversensing. Independent predictors of IAS were higher 12-lead electrocardiographic R-wave amplitude (aOR 2.55 per 1 mV; 95% confidence interval 1.15-6.38) and abnormal T-wave inversions (aOR 0.16; 95% confidence interval 0.02-0.97). There were 2 appropriate shocks in 7 secondary prevention patients and none in 81 primary prevention patients, despite 96% meeting Enhanced American College of Cardiology/American Heart Association criteria and the mean European HCM Risk-SCD score predicting 5.7% 5-year risk. No patients had sudden death or untreated sustained ventricular arrhythmias. CONCLUSION: In this multicenter HCM S-ICD study, IAS were rare and appropriate shocks confined to secondary prevention patients. The R-wave amplitude increased IAS risk, whereas T-wave inversions were protective. HCM primary prevention implantable cardioverter-defibrillator guidelines overestimated the risk of appropriate shocks in our cohort.

Hypothermia Modulates Arrhythmia Substrates During Different Phases of Resuscitation From Ischemic Cardiac Arrest.

BACKGROUND: We designed an innovative porcine model of ischemia-induced arrest to determine dynamic arrhythmia substrates during focal infarct, global ischemia from ventricular tachycardia or fibrillation (VT/VF) and then reperfusion to determine the effect of therapeutic hypothermia (TH) on dynamic arrhythmia substrates and resuscitation outcomes. METHODS AND RESULTS: Anesthetized adult pigs underwent thoracotomy and regional plunge electrode placement in the left ventricle. Subjects were then maintained at either control (CT; 37°C, n=9) or TH (33°C, n=8). The left anterior descending artery (LAD) was occluded and ventricular fibrillation occurred spontaneously or was induced after 30 minutes. Advanced cardiac life support was started after 8 minutes, and LAD reperfusion occurred 60 minutes after occlusion. Incidences of VF/VT and survival were compared with ventricular ectopy, cardiac alternans, global dispersion of repolarization during LAD occlusion, and LAD reperfusion. There was no difference in incidence of VT/VF between groups during LAD occlusion (44% in CT versus 50% in TH; P=1s). During LAD occlusion, ectopy was increased in CT and suppressed in TH (33±11 ventricular ectopic beats/min versus 4±6 ventricular ectopic beats/min; P=0.009). Global dispersion of repolarization and cardiac alternans were similar between groups. During LAD reperfusion, TH doubled the incidence of cardiac alternans compared with CT, with a marked increase in VF/VT (100% in TH versus 17% in CT; P=0.004). Ectopy and global dispersion of repolarization were similar between groups during LAD reperfusion. CONCLUSIONS: TH alters arrhythmia substrates in a porcine translational model of resuscitation from ischemic cardiac arrest during the complex phases of resuscitation. TH worsens cardiac alternans, which was associated with an increase in spontaneous VT/VF during reperfusion.

Mild hypothermia preserves myocardial conduction during ischemia by maintaining gap junction intracellular communication and Na+ channel function.

Acute cardiac ischemia induces conduction velocity (CV) slowing and conduction block, promoting reentrant arrhythmias leading to sudden cardiac arrest. Previously, we found that mild hypothermia (MH; 32°C) attenuates ischemia-induced conduction block and CV slowing in a canine model of early global ischemia. Acute ischemia impairs cellular excitability and the gap junction (GJ) protein connexin (Cx)43. We hypothesized that MH prevented ischemia-induced conduction block and CV slowing by preserving GJ expression and localization. Canine left ventricular preparations at control (36°C) or MH (32°C) were subjected to no-flow prolonged (30 min) ischemia. Optical action potentials were recorded from the transmural left ventricular wall, and CV was measured throughout ischemia. Cx43 and Na+ channel (NaCh) remodeling was assessed using both confocal immunofluorescence (IF) and/or Western blot analysis. Cellular excitability was determined by microelectrode recordings of action potential upstroke velocity (dV/dtmax) and resting membrane potential (RMP). NaCh current was measured in isolated canine myocytes at 36 and 32°C. As expected, MH prevented conduction block and mitigated ischemia-induced CV slowing during 30 min of ischemia. MH maintained Cx43 at the intercalated disk (ID) and attenuated ischemia-induced Cx43 degradation by both IF and Western blot analysis. MH also preserved dV/dtmax and NaCh function without affecting RMP. No difference in NaCh expression was seen at the ID by IF or Western blot analysis. In conclusion, MH preserves myocardial conduction during prolonged ischemia by maintaining Cx43 expression at the ID and maintaining NaCh function. Hypothermic preservation of GJ coupling and NaCh may be novel antiarrhythmic strategies during resuscitation.NEW & NOTEWORTHY Therapeutic hypothermia is now a class I recommendation for resuscitation from cardiac arrest. This study determined that hypothermia preserves gap junction coupling as well as Na+ channel function during acute cardiac ischemia, attenuating conduction slowing and preventing conduction block, suggesting that induced hypothermia may be a novel antiarrhythmic strategy in resuscitation.

PACAP induces plasticity at autonomic synapses by nAChR-dependent NOS1 activation and AKAP-mediated PKA targeting.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide found at synapses throughout the central and autonomic nervous system. We previously found that PACAP engages a selective G-protein coupled receptor (PAC1R) on ciliary ganglion neurons to rapidly enhance quantal acetylcholine (ACh) release from presynaptic terminals via neuronal nitric oxide synthase (NOS1) and cyclic AMP/protein kinase A (PKA) dependent processes. Here, we examined how PACAP stimulates NO production and targets resultant outcomes to synapses. Scavenging extracellular NO blocked PACAP-induced plasticity supporting a retrograde (post- to presynaptic) NO action on ACh release. Live-cell imaging revealed that PACAP stimulates NO production by mechanisms requiring NOS1, PKA and Ca(2+) influx. Ca(2+)-permeable nicotinic ACh receptors composed of α7 subunits (α7-nAChRs) are potentiated by PKA-dependent PACAP/PAC1R signaling and were required for PACAP-induced NO production and synaptic plasticity since both outcomes were drastically reduced following their selective inhibition. Co-precipitation experiments showed that NOS1 associates with α7-nAChRs, many of which are perisynaptic, as well as with heteromeric α3*-nAChRs that generate the bulk of synaptic activity. NOS1-nAChR physical association could facilitate NO production at perisynaptic and adjacent postsynaptic sites to enhance focal ACh release from juxtaposed presynaptic terminals. The synaptic outcomes of PACAP/PAC1R signaling are localized by PKA anchoring proteins (AKAPs). PKA regulatory-subunit overlay assays identified five AKAPs in ganglion lysates, including a prominent neuronal subtype. Moreover, PACAP-induced synaptic plasticity was selectively blocked when PKA regulatory-subunit binding to AKAPs was inhibited. Taken together, our findings indicate that PACAP/PAC1R signaling coordinates nAChR, NOS1 and AKAP activities to induce targeted, retrograde plasticity at autonomic synapses. Such coordination has broad relevance for understanding the control of autonomic synapses and consequent visceral functions.