PD-1/PDL-1 Inhibitors and Cardiotoxicity; Molecular, Etiological and Management Outlines.

Background: The US Food and Drug Administration (FDA) has approved several immunotherapeutic drugs for cancer since 2010, and many more are still being evaluated in other clinical studies. These inhibitors significantly increase response rates and result in the treatment of patients with advanced cancer. However, cancer immunotherapy leads to essential cardiac toxicity properties that have become distinct from other cancer patients' care and are mostly related to their etiology. Aim of review: As potential implications, the occurrence of cardiovascular adverse events is particularly challenging and needs a comprehensive understanding of overall cancer-related etiology, clinical outcomes with different variable severity, and management. Key scientific concepts of review: In terms of improving the overall survival of patients with cancer, clinicians should be careful in selecting either programmed cell death-1 (PD-1) or its programmed cell death ligand (PDL-1) inhibitors by evaluating their risk and clinical benefit for early intervention and decrease the level of morbidity and mortality of their patients. This review focuses on the effectiveness of PD-1/PL-1 antibodies and associated cardiotoxicity adverse events, including etiological mechanisms, diagnosis, and treatment.

Insights into sinus arrhythmia of the dog: Acetylcholine perfusion of canine right atrium results in beat-to-beat patterns that mimic sinus arrhythmia supporting exit block in the sinoatrial conduction pathways.

Sinus arrhythmia of the dog is unique because of the pronounced alternating beat-to-beat intervals. The clustering of these short (faster rates) and long (slower rates) intervals is not just influenced by autonomic input from breathing; sinus arrhythmia can persist in the panting or apneic dog. The multiplicity of central and peripheral influences on the sinus node complicates the unraveling of the mechanisms of sinus arrhythmia. Studies of the sinus node suggest that acetylcholine can slow cellular depolarization and block sinoatrial conduction. Electrocardiographic monitoring of the dog supports this notion in that abrupt bifurcation into short and long intervals develop at lower heart rates. We sought to determine whether this phenomenon could be recapitulated in canine atrial preparations perfused with acetylcholine and whether selective pharmacologic blockade of the voltage and calcium clocks could provide insight into its mechanism. Spontaneous beat to beat (A-A) intervals were obtained from monophasic action potential recordings of perfused canine right atrial preparations before and during perfusion with acetylcholine (2-5 µM). The calcium clock was blocked with ryanodine (2-3 µM). The membrane clock was blocked with diltiazem hydrochloride (ICa,L blocker; 0.25 µM) and ZD7288 (If blocker; 3 µM). Hyperpolarization was hindered by blockade of IK,Ado/IK,Ach with tertiapin Q (100 nM) before and during acetylcholine perfusion. Acetylcholine resulted in beat clusters similar to those seen in sinus arrhythmia of the dog. Beat clusters were consistent with intermittent 2:1 and 3:1 sinoatrial conduction block. Tertiapin Q abolished this patterning suggesting a role of IK,Ado/IK,ACh in the mechanism of these acetylcholine-induced beat-to-beat patterns.

Azithromycin and tezacaftor/ivacaftor is associated with first-degree heart block in an adult with cystic fibrosis.

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene is expressed in the heart, but this is not known to cause myocardial dysfunction or abnormalities in the ECG in people with CF. CFTR modulators such as tezacaftor/ivacaftor improve lung function and overall health in people with CF. Minor adverse events have been reported in the early clinical trials, but no consistent changes in the ECGs have been reported. This case highlights an unusual side effect of first degree heart block that occurred after more than 8 months of azithromycin and tezacaftor/ivacaftor in combination. Drug withdrawal and reintroduction confirmed that neither drug alone, but only the combination, caused this change. As tezacaftor/ivacaftor is also present in elexacaftor/tezacaftor/ivacaftor, care may be needed to exclude this delayed interaction with azithromycin.

Utility of Hypertonic Saline and Diazepam in COVID-19-Related Hydroxychloroquine Toxicity.

BACKGROUND: Hydroxychloroquine (HCQ) poisoning is a life-threatening but treatable toxic ingestion. The scale of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) and the controversial suggestion that HCQ is a treatment option have led to a significant increase in HCQ use. HCQ poisoning should be at the top-of-mind for emergency providers in cases of toxic ingestion. Treatment for HCQ poisoning includes sodium bicarbonate, epinephrine, and aggressive electrolyte repletion. We highlight the use of hypertonic saline and diazepam. CASE REPORT: We describe the case of a 37-year-old man who presented to the emergency department after the ingestion of approximately 16 g of HCQ tablets (initial serum concentration 4270 ng/mL). He was treated with an epinephrine infusion, hypertonic sodium chloride, high-dose diazepam, sodium bicarbonate, and aggressive potassium repletion. Persistent altered mental status necessitated intubation, and he was managed in the medical intensive care unit until his QRS widening and QTc prolongation resolved. After his mental status improved and it was confirmed that his ingestion was not with the intent to self-harm, he was discharged home with outpatient follow-up. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: For patients presenting with HCQ overdose and an unknown initial serum potassium level, high-dose diazepam and hypertonic sodium chloride should be started immediately for the patient with widened QRS. The choice of hypertonic sodium chloride instead of sodium bicarbonate is to avoid exacerbating underlying hypokalemia which may in turn potentiate unstable dysrhythmia. In addition, early intubation should be a priority in vomiting patients because both HCQ toxicity and high-dose diazepam cause profound sedation.

Complete Heart Block Secondary to Flecainide Toxicity: Is It Time for CYP2D6 Genotype Testing?

Flecainide acetate is a Vaughan-Williams class IC antiarrhythmic drug prescribed for the treatment of supraventricular arrhythmias. It has a narrow therapeutic index and proarrhythmic effects even at therapeutic doses. Flecainide is metabolized by a CYP2D6 enzyme that exhibits polymorphism. In this case report, we present, to our best knowledge, the first case of toxicity contributed by genetic polymorphism in an infant. Our patient with recurrent supraventricular tachycardia was treated with a therapeutic dose of flecainide but developed heart block requiring extracorporeal membrane oxygenation support and subsequent treatment with lipid emulsion therapy. He was found to have supratherapeutic serum flecainide concentration, and gene testing revealed the patient to be an intermediate metabolizer. With this case report, we reinforce the importance of evaluating the CYP2D6 genotype before drug initiation in the neonatal population and recommend regular monitoring of serum flecainide levels and electrocardiograms in these patients.

Nontransient third-degree heart block and persistent respiratory findings as sequelae of acute occupational exposure to pyrethroids insecticide.

We present the case of a worker with occupational exposure to a pyrethroid insecticide who acutely developed nontransient third-degree heart block. In 2000, a 57-year-old male truck driver on his delivery route was accidentally exposed to pyrethroid insecticide being sprayed for West Nile virus containment. Both the driver and his vehicle were coated with the spray. The exposure was prolonged because he did not change his clothes until after his shift ended and he used the same contaminated truck for a week. Within days, he presented with a third-degree heart block, for which he was emergently treated, and a pacemaker was placed. He had no past history of arrhythmias. In the weeks thereafter, he also developed reactive airway dysfunction syndrome (RADS). In the second decade following the exposure, the patient replaced his pacemaker, confirming the permanent nature of his heart block. In addition to the persistence of his exposure-related RADS, he developed restrictive lung disease and was diagnosed with pulmonary interstitial fibrosis in the absence of established risk factors. The patient died in October 2019 from respiratory illness. Most previous reports of pyrethroid-related disorders are limited to acute exposures, in which transient symptoms predominate. To our knowledge, this is the first report of an exposed worker experiencing permanent third-degree heart block, as well as persistent respiratory findings, as possible short- and long-term sequelae of pyrethroid exposure.

Collapse in the elderly: rivastigmine-induced heart block and a literature review of the pharmacology of acetylcholinesterase inhibitors used in Alzheimer's disease.

Falls resulting in neck of femur fractures are common in the elderly. Often multiple comorbidities can make management and diagnosis of such a polyfactorial condition difficult, particularly with Alzheimer's dementia (AD). Indeed, poorly managed AD may contribute to falls. We present our management of an 87-year-old woman, on rivastigmine for AD, who presented with a collapse episode-attributed to rivastigmine-resulting in a neck of femur fracture. Furthermore, we perform a literature review of the pharmacology of acetylcholinesterase inhibitors and how their use in AD may contribute to bradyarrhythmias.

Acute and long-term effects of fingolimod on heart rhythm and heart rate variability in patients with multiple sclerosis.

BACKGROUND: Fingolimod can lead to increased risk of cardiac events such as bradycardia or atrioventricular (AV) block. OBJECTIVE: Evaluate acute and long-term effects of fingolimod on heart rhythm (HR), heart rate variability (HRV) and development of AV-blocks. METHODS: In 64 patients with relapsing-remitting multiple sclerosis Holter ECG monitoring (HEM) and HRV analysis were performed 24h before, six h during and 72h after initiation of fingolimod. We additionally analyzed a 24h HEM after a follow up of ≥ three months. RESULTS: Heart rate (HR) decreased significantly (p < 0.001) under fingolimod treatment with nadir at five hours after starting and maintained decreased for 72h. Five (7.8%) patients suffered from new-onset AV-block requiring cessation of treatment. In four of five patients (80%), the AV-block could only be documented in the 72h-HEM with a median time of occurrence at 14h. The mean heart rate was still significant lower after a mean follow up time of 14.1 ± 9.6 months (85.0 ± 9.8 vs. 75.3 ± 16.2 bpm; p = 0.002) in comparison to baseline. CONCLUSION: The treatment with fingolimod leads to an increase of vagal activation which persists even after 14 months of treatment. These changes did not return to baseline levels on treatment with fingolimod. Based on our data an additional at least 24h hour-HEM after the initiation of fingolimod therapy should be considered.

Chronic Low Dose Prostaglandin and Neonatal Heart Block.

Long-term prostaglandin use is commonly associated with side effects such as cortical proliferation of the bones, hypertrophic pyloric stenosis, and soft tissue swelling of the extremities. We report a neonate with critical coarctation of the aorta, who developed second and third degree atrioventricular blocks associated with prolonged prostaglandin E1 (PGE1) infusion. Interestingly, these conduction blocks only occurred at low PGE1 dose. The rhythm disturbances resolved promptly with the discontinuation of PGE1 following surgical repair.

Chronic lithium intoxication: Varying electrocardiogram manifestations.

Lithium is a commonly used drug in psychiatric practice. It is used in the treatment of depression and bipolar disorder. It has a narrow therapeutic index with documented adverse effects even near therapeutic levels. It has myriad of manifestations at toxic levels. The cardiovascular effects range from relatively benign ST-T wave changes to fatal arrhythmias. We describe a case of lithium toxicity which presented as a junctional rhythm and later showed a variety of manifestations such as complete heart block, atrial fibrillation, sinus bradycardia, and finally reverted to sinus rhythm at par with serum lithium levels.

Use of adenosine to shorten the post ablation waiting period for cavotricuspid isthmus-dependent atrial flutter.

BACKGROUND: Dormant conduction unmasked by adenosine predicts clinical recurrences of cavotricuspid isthmus (CTI) dependent atrial flutter following catheter ablation. Conventional practice involves a waiting period of 20 to 30 minutes after achievement of a bidirectional line of block (BDB) to monitor for recovery of conduction. OBJECTIVE: Assess whether abolition of dormant conduction with adenosine immediately after CTI ablation and BDB can predict the lack of CTI conduction recovery during the following 30 minutes. METHODS: Consecutive patients undergoing catheter ablation for CTI-dependent atrial flutter were studied. Following the completion of CTI ablation and documentation of BDB, adenosine (≥12 mg IV) was administered immediately. In cases of dormant conduction, the CTI was ablated again until its abolition. After the achievement of BDB without dormant conduction, spontaneous CTI reconnection during the following 30 minutes and dormant conduction with adenosine at 30 minutes were evaluated. RESULTS: A CTI block was achieved in 171 patients. Nine patients (5.3%) had dormant conduction across the CTI immediately after ablation and BDB, and required further ablation. Two patients (1.2%) had subsequent spontaneous time-dependent reconnection within 30 minutes. Two other patients (1.2%) developed late dormant conduction with adenosine at 30 minutes. All 4 patients underwent further ablation. CONCLUSION: A negative adenosine challenge immediately after CTI ablation with bidirectional block, or after abolition of dormant conduction with further ablation, strongly predicted the absence of subsequent spontaneous reconnection within 30 minutes. Based on these results, the conventional waiting period is unnecessary in 97.6% patients without dormant conduction after CTI-dependent flutter ablation.

Heart failure secondary to carfilzomib-induced heart block in multiple myeloma patients.

Carfilzomib is a proteasome inhibitor and immunomodulator used to treat patients with multiple myeloma who have disease progression refractory to bortezomib. The difference in agents is that carfilzomib is an irreversible inhibitor of 20 s proteasome. The most common side effects of carfilzomib are fatigue, nausea, diarrhea, anemia, thrombocytopenia, dyspnea, and pyrexia. Less frequent side effects include cardiac manifestations for which we will explore with more detail. In this case report, we describe a 70-year-old female with multiple myeloma presenting to the emergency department with complaint of dyspnea. Patient was discovered to be in heart failure with atrioventricular block necessitating placement of a pacemaker.

Transient Complete Heart Block Secondary to Bed Bug Insecticide: A Case of Pyrethroid Cardiac Toxicity.

Pyrethroids are the major components of various commercially used insect repellants. These are less toxic to humans due to their slow absorption and rapid metabolism. However, cases of suicidal and accidental poisoning with household insecticides are not uncommon. We report a case of a 59-year-old female who presented with syncope after an accidental exposure to bed bug repellant spray at home. She was found to be in complete heart block and was treated conservatively. There was complete resolution of symptoms and atrioventricular conduction abnormality on day 2 of hospitalization. She was discharged in a stable condition with an uneventful follow-up course. Cardiac involvement in pyrethroid toxicity is rare. We describe various clinical manifestations and the pathophysiology of toxicity caused by pyrethroid-containing insecticides.

Transient A-V dissociation and severe hypotension due to consumption of Ayurvedic medicine--Vatsanabha (aconitum ferox).

A 24 year old married, well educated, female patient presented with complaints of giddiness and blackouts. On evaluation, patient had hypotension and bradycardia. ECG findings were suggestive of complete A-V dissociation. On detailed history patient revealed consumption. of Ayurvedic medicine Vatsanabha for arthritis. This study impresses upon the need for complete history talking and generating awareness regarding the correct and observed use of any drug including alternative medicines.

Kounis syndrome: acute inferior myocardial infarction with atroventricular node block due to ceftriaxone: a first reported case.

Cefriaxone is a third-generation cephalosporin that might rarely cause a severe allergic reaction. Acute cardiac emergencies are quite rare in the setting of drug allergies. Here, we report the first case of myocardial infarction and AV-block after intravenous cefriaxone administration.