Propofol for Induction and Maintenance of Anesthesia in Patients With Brugada Syndrome: A Single-Center, 25-Year, Retrospective Cohort Analysis.

BACKGROUND: Propofol administration in patients with Brugada syndrome (BrS) is still a matter of debate. Despite lacking evidence for its feared arrhythmogenicity, up to date, expert cardiologists recommend avoiding propofol. The main aim of this study is to assess the occurrence of malignant arrhythmias or defibrillations in patients with BrS, during and 30 days after propofol administration. The secondary aim is to investigate the occurrence of adverse events during propofol administration and hospitalization, as the 30-day readmission and 30-day mortality rate. METHODS: We performed a retrospective cohort study on patients with BrS who received propofol anytime from January 1, 1996 to September 30, 2020. Anesthesia was induced by propofol in both groups. In the total intravenous anesthesia (TIVA) group, anesthesia was maintained by propofol, while in the BOLUS group, volatile anesthesia was provided. The individual anesthetic charts and the full electronic medical records up to 30 postprocedural days were scrutinized. RESULTS: One hundred thirty-five BrS patients who underwent a total of 304 procedures were analyzed. The TIVA group included 27 patients for 33 procedures, and the BOLUS group included 108 patients for 271 procedures. In the TIVA group, the median time of propofol infusion was 60 minutes (interquartile range [IQR] = 30-180). The estimated plasma or effect-site concentration ranged between 1.0 and 6.0 µg·mL-1 for target-controlled infusion (TCI). The infusion rate for manually driven TIVA varied between 0.8 and 10.0 mg·kg-1·h-1. In the BOLUS group, the mean propofol dose per kilogram total body weight was 2.4 ± 0.9 mg·kg-1. No malignant arrhythmias or defibrillations were registered in both groups. The estimated 95% confidence interval (CI) of the risk for malignant arrhythmias in the BOLUS and TIVA groups was 0-0.011 and 0-0.091, respectively. CONCLUSIONS: The analysis of 304 anesthetic procedures in BrS patients, who received propofol, either as a TIVA or as a bolus during induction of volatile-based anesthesia, revealed no evidence of malignant arrhythmias or defibrillations. The present data do not support an increased risk with propofol-based TIVA compared to propofol-induced volatile anesthesia. Prospective studies are needed to investigate the electrophysiologic effects of propofol in BrS patents.

Electrocardiographic findings of methanol toxicity: a cross-sectional study of 356 cases in Iran.

BACKGROUND: Methanol is widely used in industry; however, methanol poisoning is not common. In this regard, a number of outbreaks have been recently reported due to inappropriate processing of alcoholic beverages. Shiraz, a city located in the southern part of Iran, faced one of such outbreaks in 2020 during COVID-19 pandemic. There is no sufficient literature on the electrocardiographic findings in methanol toxicity. This study aimed to address this gap in the literature. METHOD: A total of 356 cases with methanol toxicity referred to Shiraz University of Medical Science Tertiary Hospitals (Faghihi and Namazi) in March and April, 2020. The clinical findings of blindness and impaired level of consciousness, lab data such as arterial blood gas, electrolytes, and creatinine, and the most common findings from ECGs were collected. RESULTS: The most common ECG findings were J point elevation (68.8%), presence of U wave (59.2%), QTc prolongation (53.2% in males and 28.6% in females), and fragmented QRS (33.7%). An outstanding finding in this study was the presence of myocardial infarction in 5.3% of the cases. This finding, to the best of our knowledge, has only been reported in a few case reports. Brugada pattern (8.1%) and Osborn wave (3.7%) were the other interesting findings. In multivariate analysis, when confounding factors were adjusted, myocardial infarction, atrioventricular conduction disturbances, sinus tachycardia, and the prolonged QTC > 500 msecond were four independent factors correlated with methanol toxicity severity measured with arterial blood PH on arterial blood gas measurements, with odds ratios of 12.82, 4.46, 2.32 and 3.15 (P < 0.05 for all), respectively. CONCLUSION: Electrocardiographic variations during methanol intoxication are remarkable and well-correlated with poisoning severity. Myocardial infarction was an egregious and yet a common concerning finding in this sample, which need to be ruled out in methanol toxicity.

Clinical Characteristics and Electrophysiological Mechanisms Underlying Brugada ECG in Patients With Severe Hyperkalemia.

Background Several metabolic conditions can cause the Brugada ECG pattern, also called Brugada phenotype (BrPh). We aimed to define the clinical characteristics and outcome of BrPh patients and elucidate the mechanisms underlying BrPh attributed to hyperkalemia. Methods and Results We prospectively identified patients hospitalized with severe hyperkalemia and ECG diagnosis of BrPh and compared their clinical characteristics and outcome with patients with hyperkalemia but no BrPh ECG. Computer simulations investigated the roles of extracellular potassium increase, fibrosis at the right ventricular outflow tract, and epicardial/endocardial gradients in transient outward current. Over a 6-year period, 15 patients presented severe hyperkalemia with BrPh ECG that was transient and disappeared after normalization of their serum potassium. Most patients were admitted because of various severe medical conditions causing hyperkalemia. Six (40%) patients presented malignant arrhythmias and 6 died during admission. Multiple logistic regression analysis revealed that higher serum potassium levels (odds ratio, 15.8; 95% CI, 3.1-79; P=0.001) and male sex (odds ratio, 17; 95% CI, 1.05-286; P=0.045) were risk factors for developing BrPh ECG in patients with severe hyperkalemia. In simulations, hyperkalemia yielded BrPh by promoting delayed and heterogeneous right ventricular outflow tract activation attributed to elevation of resting potential, reduced availability of inward sodium channel conductance, and increased right ventricular outflow tract fibrosis. An elevated transient outward current gradient contributed to, but was not essential for, the BrPh phenotype. Conclusions In patients with severe hyperkalemia, a BrPh ECG is associated with malignant arrhythmias and all-cause mortality secondary to resting potential depolarization, reduced sodium current availability, and fibrosis at the right ventricular outflow tract.

Integration of "Omics" Strategies for Biomarkers Discovery and for the Elucidation of Molecular Mechanisms Underlying Brugada Syndrome.

PURPOSE: The Brugada syndrome (BrS) is a severe inherited cardiac disorder. Given the high genetic and phenotypic heterogeneity of this disease, three different "omics" approaches are integrated in a synergic way to elucidate the molecular mechanisms underlying the pathophysiology of BrS as well as for identifying reliable diagnostic/prognostic markers. EXPERIMENTAL DESIGN: The profiling of plasma Proteome and MiRNome is perfomed in a cohort of Brugada patients that were preliminary subjected to genomic analysis to assess a peculiar gene mutation profile. RESULTS: The integrated analysis of "omics" data unveiled a cooperative activity of mutated genes, deregulated miRNAs and proteins in orchestrating transcriptional and post-translational events that are critical determining factors for the development of the Brugada pattern. CONCLUSIONS AND CLINICAL RELEVANCE: This study provides the basis to shed light on the specific molecular fingerprints underlying BrS development and to gain further insights on the pathogenesis of this life-threatening cardiac disease.

Low Serum Levels of Eicosapentaenoic Acid and Docosahexaenoic Acid are Risk Factors for Cardiogenic Syncope in Patients with Brugada Syndrome.

The n-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have antiarrhythmic effects, possibly via modulation of the cardiac ion channels. Nevertheless, it is unknown whether low serum levels of n-3 PUFAs are risk factors for ventricular fibrillation in patients with Brugada syndrome (BrS). We retrospectively reviewed data from 62 men with BrS and evaluated their serum levels of EPA and DHA, and the risk factors for sudden cardiac death, including a history of cardiogenic syncope. Nineteen patients had a history of cardiogenic syncope, and their EPA and DHA levels were significantly lower than those of the patients without syncope. Multivariate logistic regression analysis revealed that low EPA and DHA levels were associated with the incidence of syncope. The receiver-operator characteristic curve showed the area under the curves of EPA and DHA for history of syncope were 0.84 and 0.72, respectively. In conclusion, low levels of EPA and DHA are risk factors for cardiogenic syncope in patients with BrS, which suggests that n-3 PUFAs play important roles in preventing ventricular fibrillation in BrS.

Not all ST-segment elevations are myocardial infarction: Hyperkalemia and Brugada phenocopy.

Several clinical conditions other than Brugada syndrome (BrS) can mimic acute ST-segment elevation myocardial infarction and Brugada phenocopies are a part of those conditions that can mimic either true BrS or acute myocardial infarction. Our manuscript shows an interesting and didactic case report of type-1 Class A Brugada phenocopy (BrP) induced by hyperkalemia and allow us to teach the systematic approach to the proper diagnosis of BrP. A prompt recognition of this clinical and electrocardiographic entity may expedite the initiation of appropriate treatments as illustrated in this case report.

High Frequency of Early Repolarization and Brugada-Type Electrocardiograms in Hypercalcemia.

BACKGROUND: J wave, or early repolarization has recently been associated with an increased risk of lethal arrhythmia and sudden death, both in idiopathic ventricular fibrillation and in the general population. Hypercalcemia is one of the causes of J point and ST segment elevation, but the relationship has not been well studied. The aim of this study was to examine the effects of hypercalcemia on J point elevation. METHODS: Electrocardiographic findings were compared in 89 patients with hypercalcemia and 267 age- and sex-matched healthy controls with normocalcemia. The association of J point elevation with arrhythmia events in patients with hypercalcemia was also studied. RESULTS: The PR interval and the QRS duration were longer in patients with hypercalcemia than in normocalcemic controls. Both the QT and the corrected QT intervals were shorter in patients with hypercalcemia compared with normocalcemic controls. Conduction disorders, ST-T abnormalities, and J point elevation were more common in patients with hypercalcemia than normocalcemic controls. Following the resolution of hypercalcemia, the frequency of J point elevation decreased to a level similar to that noted in controls. During hospitalization, no arrhythmia event occurred in patients with hypercalcemia. CONCLUSION: Hypercalcemia was associated with J point elevation.

Circulating heart-type fatty acid-binding protein levels predict ventricular fibrillation in Brugada syndrome.

BACKGROUND: The association between ongoing myocardial damage and outcomes in patients with Brugada syndrome who had received an implantable cardioverter-defibrillator (ICD) is unclear. METHODS: Consecutive patients with Brugada syndrome (n=31, 50±13 years) who had received an ICD were prospectively enrolled. Minor myocardial membrane injury [heart-type fatty acid-binding protein (H-FABP) >2.4ng/mL] and myofibrillar injury (troponin T >0.005ng/mL) were defined using receiver operating characteristic curves. Patients were followed for a median period of 5 years to an endpoint of appropriate ICD shock. RESULTS: Myocardial membrane injury (29%) and myofibrillar injury (26%) were similarly prevalent among patients with Brugada syndrome who had received ICDs. Appropriate ICD shocks occurred in 19% of patients during the follow-up period. Multivariate Cox regression analysis showed that serum H-FABP level >2.4ng/mL, but not troponin T level, was an independent prognostic factor for appropriate ICD shock due to ventricular fibrillation [hazard ratio (HR) 25.2, 95% confidence interval (CI) 1.33-1686, p=0.03]. CONCLUSIONS: Evaluating myocardial damage using H-FABP may be a promising tool for predicting ventricular arrhythmia in patients with Brugada syndrome who have received ICDs.

Not all ST-segment changes are myocardial injury: hypercalcaemia-induced ST-segment elevation.

ST-segment elevation myocardial infarction is an important, life-threatening diagnosis that requires quick diagnosis and management. We describe the case of an 83-year-old man with coronary artery disease, ischaemic cardiomyopathy with left ventricular ejection fraction of 15%, newly diagnosed multiple myeloma that had an initial ECG showing ST-segment elevation in anterior leads V1-3 and ST-segment depression in lateral leads concerning for an ST-segment elevation myocardial infarction. Troponins were negative and his calcium was 3.55 mmol/L. It was thought that the ECG changes were not indicative of cardiac ischaemia but, rather, hypercalcaemia. He was treated with fluids, diuretics and zolendronic acid, with subsequent resolution of ST-segment changes. This case demonstrates that one must consider disease other than myocardial ischaemia as the culprit of ST-segment changes if physical examination and history do not point towards myocardial injury, as unnecessary invasive revascularisation procedures have inherent risks.

The relationship between repolarization parameters and serum electrolyte levels in patients with J wave syndromes.

BACKGROUND: Intravenous administration of magnesium (Mg(2+)) is effective for polymorphic ventricular tachycardia via homogenization of transmural ventricular repolarization. Mg(2+) likely plays some role in the heterogeneity of repolarization in J wave syndromes. OBJECTIVE: To investigate the relationship between the repolarization parameters and serum Mg(2+), potassium (K(+)), and calcium (Ca(2+)) levels in J wave syndromes. METHODS: Thirteen J-wave syndrome patients (Brugada and early repolarization [ER] syndromes), with documented episodes of ventricular fibrillation (VF), and 13 ER pattern (ERP) or Brugada type ECG patients were enrolled (25 males, mean age 48 ± 15 years). The 12-lead ECG-derived parameters including the QT, QT dispersion (QTd), Tpeak-Tend (Tp-e) interval, Tp-e dispersion (Tp-ed), Tp-e/QT ratio, and activation recovery interval (ARI) dispersion were calculated; the correlations between these parameters and electrolytes including Mg(2+), K(+), and Ca(2+) were analyzed. RESULTS: Although there was no association between serum K(+) or Ca(2+) and QTd, there was a strong negative correlation between serum Mg(2+) and QTd in J wave syndrome patients with a history of VF (r = -0.715, p = 0.006). Also, there was a tendency for a negative correlation between Mg(2+) and Tp-ed or ARI dispersion in J wave syndrome patients with a history of VF (r = -0.513, p = 0.072 and r = -0.53, p = 0.063, respectively). On the other hand, in 13 patients with a Brugada type ECG or ERP, no correlation was observed between serum Mg(2+) and the QTd, Tp-ed or ARI dispersion. CONCLUSION: Serum Mg(2+) may play an important role in the cardiac repolarization process in J wave syndromes.

Brugada syndrome with elevated cardiac biomarkers.

A 45-year-old man presented to our hospital with a history of palpitations, presyncope and chest pain. Vital signs and physical examination were unremarkable. Initial ECG  revealed sinus rhythm with non-specific ST changes. Subsequent ECGs showed rsr' in V1 and saddle-back pattern of ST elevation in lead V2, indicative of type 2 Brugada ECG pattern. Telemetry monitoring revealed multiple runs of asymptomatic non-sustained polymorphic ventricular tachycardia. Ajmaline challenge test confirmed the diagnosis of Brugada syndrome. The subsequent rise and fall of cardiac biomarkers was suggestive of acute myocardial infarction which was refuted by having normal coronaries by cardiac catheterisation. Echocardiogram showed normal cardiac structures and function without any evidence of myopericarditis. Automated intracardiac defibrillator was recommended which the patient declined.

Biomarker discovery by plasma proteomics in familial Brugada Syndrome.

Brugada Syndrome (BS) is a polygenic inherited cardiac disease characterized by life-threatening arrhythmias and high incidence of sudden death. In this study, two-dimensional gel electrophoresis (2D-PAGE) coupled to mass spectrometry (LC-MS/MS) was used to investigate specific changes in the plasma proteome of BS patients and family members sharing the same gene mutation (SCN5AQ1118X), with the aim to identify novel disease biomarkers. Our data demonstrate that the levels of several proteins were significantly altered in BS patients compared with controls. In particular, apolipoprotein E, prothrombin, vitronectin, complement-factor H, vitamin-D-binding protein, voltage-dependent anion-selective channel protein 3 and clusterin were considerably increased in plasma sample of BS patients, whereas alpha-1-antitrypsin, fibrinogen and angiotensinogen were considerably decreased; moreover, post-translational modifications of antithrombin-III were detected in all affected individuals. On the light of these results, we hypothesize that these proteins might be considered as potential markers for the identification of disease status in BS.

Liquid chromatographic assay with fluorescence detection to determine ajmaline in serum from patients with suspected Brugada syndrome.

Ajmaline is a sodium channel blocking, class 1A anti-arrhythmic drug. It has gained renewed interest in the field of cardiology as a diagnostic agent to reveal the electrocardiographic characteristics in patients with suspected Brugada syndrome. We developed a simple and precise high-performance liquid chromatographic assay to determine ajmaline in serum of patients. The samples were pre-treated using protein precipitation with perchloric acid and the extract was injected into the chromatographic system. The system consisted of an end-capped octadecyl silica column with isocratic elution using perchloric acid in a water-acetonitrile mixture. Ajmaline was detected by fluorescence at 290 and 355 nm for excitation and emission, respectively. The assay was validated in a 21-5300 ng/ml concentration range, the lower limit of quantification was 25 ng/ml. Within day precisions were 1.3-3.9%, between day precisions 2-7% and accuracies were between 95 and 99% for the whole calibration range. The drug was shown to be chemically stable under all relevant conditions. This assay has been successfully applied to pharmacokinetic-pharmacodynamic evaluations of intravenous ajmaline administration to patients with suspected Brugada syndrome.

Disorders of the autonomic nervous system in patients with Brugada syndrome: a pilot study.

INTRODUCTION: The aim of this study was to examine autonomic disorders in patients with Brugada syndrome by performing a cardiac sympathetic innervation evaluation, a head-up tilt-test (HUT) and heart rate variability (HRV) analysis. METHODS AND RESULTS: We enrolled 20 patients with Brugada syndrome (mean age 42.5 +/- 8.8 years), 9 with spontaneous and 11 with an induced type 1 electrocardiogram (ECG) in the setting of symptoms and 20 age-matched controls. All subjects underwent a HUT with parallel measurements of plasma catecholamines and cortisol, a (123)I-metaiodobenzylguanidine single photon emission tomography, and HRV evaluation. Ten control subjects participated in the innervation portion of the study. The tilt-test with clomipramine challenge was positive in 15 of 20 (75%) patients (7 spontaneous, 8 induced) and in 1 in controls (P < 0.01). A sympathoadrenal imbalance was shown in positive tests. The pattern of innervation in all groups was heterogenic and similar to controls with a trend towards lower measurements in patients with a spontaneous type 1 ECG and a positive HUT. HRV analysis did not reveal any significant differences during day and night. Four patients (20%) had sustained ventricular arrhythmias during a follow-up of 31.1 +/- 8.6 months, but no correlations with innervation or response to tilting were found. CONCLUSION: A high susceptibility to vasovagal syncope was observed in patients with Brugada syndrome, which could be disease-related symptoms. Conversely, sympathetic innervation was observed to follow a physiological, heterogenic pattern; however, these factors did not have prognostic value for life-threatening arrhythmias.

Men with Brugada-like electrocardiogram have higher risk of prostate cancer.

BACKGROUND: Elevated plasma testosterone levels are thought to play a role in the male preponderance of cases of Brugada syndrome (BS) and the development of prostate cancer. METHODS AND RESULTS: The 34 Brugada-like electrocardiogram (ECG) cases were identified among 2,681 male survivors of the atomic bomb who had undergone at least 1 biennial health examination between July 1958 and December 1999 in Nagasaki, Japan. They were followed for incident prostate cancer from July 1958 through December 2004, and the risk of prostate cancer for Brugada-like ECG, age, smoking habit, and radiation exposure was analyzed using Cox proportional hazards analysis. Among the men with or without Brugada-like ECG there were 4 (11.8%) and 54 (2.0%) cases of prostate cancer, respectively. With age adjustment there was a higher risk of prostate cancer for Brugada-like ECG (relative risk (RR): 5.42, 95% confidence interval (CI) 1.96-15.00, P=0.001). With further adjustment for smoking habit and radiation dose, Brugada-like ECG remained a significant risk factor for prostate cancer (RR: 6.47, 95%CI 1.97-21.21, P=0.002). CONCLUSIONS: Brugada-like ECG confers a higher risk of prostate cancer independent of age, smoking habit, and radiation exposure. Men with a Brugada-like ECG should be regularly examined for prostate cancer and vice versa, especially elderly subjects.

The hyperkalemic Brugada sign.

BACKGROUND: A few case reports have indicated that hyperkalemia can induce a Brugada pattern in the electrocardiogram. The specific clinical and electrocardiographic features of the hyperkalemic Brugada sign, however, have not been previously described. METHODS: A case series was collected from hospitalized hyperkalemic patients with a type I Brugada pattern in the electrocardiogram, and a literature review was performed. Electrocardiograms were examined for rhythm and morphology, and clinical characteristics were analyzed. RESULTS: Nine new cases with the hyperkalemic Brugada sign were identified with an additional 15 cases found in the literature. Of the 9 cases, 8 were male patients, and all were critically ill; 5 of the 9 died within 48 hours. The mean (+/-SD) serum potassium level was 7.8 +/- 0.5 mEq/L. The mean QRS width was 144 +/- 31 milliseconds, and all had abnormal QRS axis. In 6 cases, there was a wide complex rhythm without visible P waves. The clinical and electrocardiographic characteristics of 15 cases found in the literature were remarkably similar to those in our series. CONCLUSIONS: The hyperkalemic Brugada pattern differs in substantial ways from the electrocardiogram of patients with the genetic Brugada syndrome. Many patients have wide complex rhythms without visible P waves, marked QRS widening, and an abnormal QRS axis. Most patients are male, and many are critically ill. Prompt recognition of this clinical and electrocardiographic entity may expedite the initiation of appropriate treatment for hyperkalemia.