Comparative Cohort Study of Post-Acute Covid-19 Infection with a Nested, Randomized Controlled Trial of Ivabradine for Those With Postural Orthostatic Tachycardia Syndrome (The COVIVA Study) (preprint)

Background: Significant clinical similarities have been observed between the recently described Long-Haul COVID-19 (LHC) syndrome, Postural Orthostatic Tachycardia Syndrome (POTS) and Inappropriate Sinus Tachycardia (IST). Shared symptoms include light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, chest pain, dyspnea, brain-fog, and fatigue. Ivabradine is a selective sinoatrial node blocker FDA-approved for management of tachycardia associated with stable angina and heart failure not fully managed by beta blockers. In our study we aim to identify risk factors underlying LHC, as well as the effectiveness of ivabradine in controlling heart rate dysregulations and POTS/IST related symptoms. Methods/Design: A detailed prospective phenotypic evaluation combined with multi-omic analysis of 200 LHC volunteers will be conducted to identify risk factors for autonomic dysfunction. A comparator group of 50 volunteers with documented COVID-19 but without LHC will be enrolled to better understand the risk factors for LHC and autonomic dysfunction. Those in the cohort who meet diagnostic criteria for POTS or IST will be included in a nested prospective, randomized, placebo-controlled trial to assess the impact of ivabradine on symptoms and heart rate, assessed non-invasively based on physiologic response and ambulatory electrocardiogram. Additionally, studies on catecholamine production, mast cell and basophil degranulation, inflammatory biomarkers, and indicators of metabolic dysfunction will be measured to potentially provide molecular classification and mechanistic insights. Discussion: Optimal therapies for dysautonomia, particularly associated with LHC, have yet to be defined. In the present study, ivabradine, one of numerous proposed interventions, will be systematically evaluated for therapeutic potential in LHC-associated POTS and IST. Additionally, this study will further refine the characteristics of the LHC-associated POTS/IST phenotype, genotype and transcriptional profile, including immunologic and multi-omic analysis of persistent immune activation and dysregulation. The study will also explore and identify potential endotheliopathy and abnormalities of the clotting cascade.

Comparative Cohort Study of Post-Acute Covid-19 Infection with a Nested, Randomized Controlled Trial of Ivabradine for Those With Postural Orthostatic Tachycardia Syndrome (The COVIVA Study) (preprint)

Background:  Significant clinical similarities have been observed between the recently described ‘Long-Haul’ COVID-19 (LHC) syndrome, Postural Orthostatic Tachycardia Syndrome (POTS) and Inappropriate Sinus Tachycardia (IST). Shared symptoms include light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, chest pain, dyspnea, “brain-fog”, and fatigue. Ivabradine is a selective sinoatrial node blocker FDA-approved for management of tachycardia associated with stable angina and heart failure not fully managed by beta blockers. In our study we aim to identify risk factors underlying LHC, as well as the effectiveness of ivabradine in controlling heart rate dysregulations and POTS/IST related symptoms. Methods/Design:  A detailed prospective phenotypic evaluation combined with multi-omic analysis of 200 LHC volunteers will be conducted to identify risk factors for autonomic dysfunction.  A comparator group of 50 volunteers with documented COVID-19 but without LHC will be enrolled to better understand the risk factors for LHC and autonomic dysfunction.  Those in the cohort who meet diagnostic criteria for POTS or IST will be included in a nested prospective, randomized, placebo-controlled trial to assess the impact of ivabradine on symptoms and heart rate, assessed non-invasively based on physiologic response and ambulatory electrocardiogram. Additionally, studies on catecholamine production, mast cell and basophil degranulation, inflammatory biomarkers, and indicators of metabolic dysfunction will be measured to potentially provide molecular classification and mechanistic insights. Discussion: Optimal therapies for dysautonomia, particularly associated with LHC, have yet to be defined. In the present study, ivabradine, one of numerous proposed interventions, will be systematically evaluated for therapeutic potential in LHC-associated POTS and IST. Additionally, this study will further refine the characteristics of the LHC-associated POTS/IST phenotype, genotype and transcriptional profile, including immunologic and multi-omic analysis of persistent immune activation and dysregulation. The study will also explore and identify potential endotheliopathy and abnormalities of the clotting cascade. Trial registration:ClinicalTrials.gov, ID:NCT05481177 Registered on 29 July 2022.

Targeted Treatment of Inappropriate Sinoatrial Node Tachycardia Based on Electrophysiological and Structural Mechanisms.

The purpose of this review is to determine the causal mechanisms and treatment of inappropriate sinoatrial tachycardia (IST), defined as a non-physiological elevation in resting heart rate. IST is defined as a resting daytime sinus rate >100 beats/minute and an average 24-hour heart rate >90 beats/minute. Potential causal mechanisms include sympathetic receptor hypersensitivity, blunted parasympathetic tone, or enhanced intrinsic automaticity within the sinoatrial node (SAN) pacemaker-conduction complex. These anomalies may coexist in the same patient. Recent ex-vivo near-infrared transmural optical imaging of the SAN in human and animal hearts provides important insights into the functional and molecular features of this complex structure. In particular, it reveals the existence of preferential sinoatrial conduction pathways that ensure robust SAN activation with electrical conduction. The mechanism of IST is debated because even high-resolution electroanatomical mapping approaches cannot reveal intramural conduction in the 3-dimensional SAN complex. It may be secondary to enhanced automaticity, intranodal re-entry, or sinoatrial conduction pathway re-entry. Different pharmacological approaches can target these mechanisms. Long-acting ß blockers in IST can act on both primarily increased automaticity and dysregulated autonomic system. Ivabradine targets sources of increased SAN automaticity. Conventional or hybrid ablation may target all the described abnormalities. This review provides a state-of-the-art overview of putative IST mechanisms. In conclusion, based on current knowledge, pharmacological and ablation approaches for IST, including the novel hybrid SAN sparing ablation, are discussed.

Prognostic value of initial electrocardiography in predicting long-term all-cause mortality in COVID-19.

BACKGROUND: The electrocardiography (ECG) has short-term prognostic value in coronavirus disease 2019 (COVID-19), yet its ability to predict long-term mortality is unknown. This study aimed to elucidate the predictive role of initial ECG on long-term all-cause mortality in patients diagnosed with COVID-19. METHODS: In this prospective cohort study, adults with COVID-19 who underwent ECG testing within a 17-hospital health system in Northeast Ohio and Florida between 03/2020-06/2020 were identified. An expert ECG reader analyzed all studies blinded to patient status. The associations of ECG characteristics with long-term all-cause mortality and intensive care unit (ICU) admission were assessed using Cox proportional hazards regression model and multivariable logistic regression models, respectively. Status of long-term mortality was adjudicated on 01/07/2022. RESULTS: Of 837 patients (median age 65 years, 51% female, 44% Black), 683 (81.6%) were hospitalized, 281 (33.6%) required ICU admission, 67 (8.0%) died in-hospital, and 206 (24.6%) died at final follow-up after a median (IQR) of 21 (9-103) days after ECG. Overall, 179 (20.7%) patients presented with sinus tachycardia, 12 (1.4%) with atrial flutter, and 45 (5.4%) with atrial fibrillation (AF). After multivariable adjustment, sinus tachycardia (E-value for HR=3.09, lower CI=2.2) and AF (E-value for HR=3.13, lower CI=2.03) each independently predicted all-cause mortality. At final follow-up, patients with AF had 64.5% probability of death compared with 20.5% for those with normal sinus rhythm (P<.0001). CONCLUSIONS: Sinus tachycardia and AF on initial ECG strongly predict long-term all-cause mortality in COVID-19. The ECG can serve as a powerful long-term prognostic tool in COVID-19.

A Patient with Newly Diagnosed Hypertension and Pre-Existing Type 2 Diabetes Mellitus Had a Confirmed COVID-19: A Case Report and Discussion (preprint)

COVID-19 aggravates pre-existing diabetes mellitus and contributes to newly discovered hypertension by increasing blood pressure by inhibiting the activity of angiotensin-converting enzymes 2 in the rennin-angiotensin system. Diabetes patients may be more vulnerable to COVID-19 due to chronic comorbidities such as obesity and cardiovascular disease such as hypertension. On March 23, 2022, a retired black African woman in her sixties was taken into the emergency room with the chief complaints of frequent midnight urine, hazy vision, headache, fever, and tingling in her hands and feet. A throat swab polymerase chain reaction test that revealed positive results after 28 hours was used to confirm COVID-19. Her electrocardiogram showed sinus tachycardia with a heart rate of 105 beats per minute. Fluid resuscitation (0.9% normal saline) of 1000 mL and drip insulin administration were commenced as soon as she was brought to an intensive care unit. In this case report, the patient had been previously diagnosed with type 2 diabetes mellitus. COVID-19 affects the beta cells, forcing them to release insulin and increasing the insulin insufficiency, which leads to her blood glucose raising. Type 2 diabetes mellitus is therefore the most frequent comorbidity of COVID-19 in this case report. Poor blood glucose management in the case of COVID-19 may increase the pathogen's susceptibility, the likelihood that patients will be admitted to the hospital, and the likelihood that mortality will be enhanced.

A case report of COVID-19 associated with AIDS-related pulmonary tuberculosis (preprint)

Patients immunocompromised by HIV or with TB lung disease could be more susceptible to severe COVID-19 infection. The COVID-19 pandemic poses a serious hazard to tuberculosis sufferers. A 67-year-old black African house wife with an HIV/AIDS diagnosis arrived at the emergency room on September 28, 2022. The admitted woman had significant complaints included muscle weakness, a loss of weight about 33 pounds during the preceding week, headache, and a cough. Reduced breath sounds were audible on chest auscultation in the right middle and upper lungs. His electrocardiogram showed sinus tachycardia and anterior-lateral lead ST-depression. She had two nasopharyngeal swabs for COVID-19 testing, which were positive. For the first five days of her stay in the hospital, the patient needed continuous oxygen delivered through a nasal cannula at a rate of four liters per minute, and she is still taking her ART regimen. For TB treatment, she took rifampicin 150 mg, isoniazid 75 mg, pyrazinamide 400 mg, and ethambutol 275 mg during a two-month intensive phase of her TB therapy, then rifampicin 150 mg and isoniazid 75 mg for a four-month continuous phase.

Sinus Tachycardia: a Multidisciplinary Expert Focused Review.

Sinus tachycardia (ST) is ubiquitous, but its presence outside of normal physiological triggers in otherwise healthy individuals remains a commonly encountered phenomenon in medical practice. In many cases, ST can be readily explained by a current medical condition that precipitates an increase in the sinus rate, but ST at rest without physiological triggers may also represent a spectrum of normal. In other cases, ST may not have an easily explainable cause but may represent serious underlying pathology and can be associated with intolerable symptoms. The classification of ST, consideration of possible etiologies, as well as the decisions of when and how to intervene can be difficult. ST can be classified as secondary to a specific, usually treatable, medical condition (eg, pulmonary embolism, anemia, infection, or hyperthyroidism) or be related to several incompletely defined conditions (eg, inappropriate ST, postural tachycardia syndrome, mast cell disorder, or post-COVID syndrome). While cardiologists and cardiac electrophysiologists often evaluate patients with symptoms associated with persistent or paroxysmal ST, an optimal approach remains uncertain. Due to the many possible conditions associated with ST, and an overlap in medical specialists who see these patients, the inclusion of experts in different fields is essential for a more comprehensive understanding. This article is unique in that it was composed by international experts in Neurology, Psychology, Autonomic Medicine, Allergy and Immunology, Exercise Physiology, Pulmonology and Critical Care Medicine, Endocrinology, Cardiology, and Cardiac Electrophysiology in the hope that it will facilitate a more complete understanding and thereby result in the better care of patients with ST.

Inappropriate sinus tachycardia in post-COVID-19 syndrome.

Inappropriate sinus tachycardia (IST) is a common observation in patients with post-COVID-19 syndrome (PCS) but has not yet been fully described to date. To investigate the prevalence and the mechanisms underlying IST in a prospective population of PCS patients. Consecutive patients admitted to the PCS Unit between June and December 2020 with a resting sinus rhythm rate ≥ 100 bpm were prospectively enrolled in this study and further examined by an orthostatic test, 2D echocardiography, 24-h ECG monitoring (heart rate variability was a surrogate for cardiac autonomic activity), quality-of-life and exercise capacity testing, and blood sampling. To assess cardiac autonomic function, a 2:1:1 comparative sub-analysis was conducted against both fully recovered patients with previous SARS-CoV-2 infection and individuals without prior SARS-CoV-2 infection. Among 200 PCS patients, 40 (20%) fulfilled the diagnostic criteria for IST (average age of 40.1 ± 10 years, 85% women, 83% mild COVID-19). No underlying structural heart disease, pro-inflammatory state, myocyte injury, or hypoxia were identified. IST was accompanied by a decrease in most heart rate variability parameters, especially those related to cardiovagal tone: pNN50 (cases 3.2 ± 3 vs. recovered 10.5 ± 8 vs. non-infected 17.3 ± 10; p < 0.001) and HF band (246 ± 179 vs. 463 ± 295 vs. 1048 ± 570, respectively; p < 0.001). IST is prevalent condition among PCS patients. Cardiac autonomic nervous system imbalance with decreased parasympathetic activity may explain this phenomenon.

Characteristic Electrocardiography Findings of COVID-19 Patients.

BACKGROUND: Determining a relationship between coronavirus disease 2019 (COVID-19) and the ECG findings of the patients with this disease can assist in early diagnosis and patient management based on these findings. This study aimed to investigate whether COVID-19 patients had characteristic ECG findings in the acute period. METHODS: A total of 124 patients were divided into two groups as those diagnosed with COVID-19 and controls. The ECGs of these patients were evaluated in terms of rate, rhythm, presence of ST changes, PR interval, QRS width, QTc and QT interval, and presence of right and left bundle branch blocks. RESULTS: On the ECG, the median heart rate of the COVID-19 patients was 104/min (IQR: 99-114), and there was a significant difference compared to the control group (P<0.001). The median PR interval was 157/ms, the QRS width was 86 ± 9/ms in the COVID-19 patients, with no significant difference compared to the controls (P = 0.161 and P = 0.631, respectively). The median QT interval of the COVID-19 patients was normal (400/ms), but a significant difference was detected compared to the controls (P = 0.005). The QTc, ST change, AF, and presence of right and left bundle branch blocks were not significantly different between the two groups. CONCLUSION: Considering the importance of ECG findings in order to diagnose COVID-19 disease early, we can state that sinus tachycardia is very common in COVID-19 patients, but there is no characteristic ECG finding for COVID-19, including tachycardia.

Post-COVID-19 Tachycardia Syndrome: A Distinct Phenotype of Post-Acute COVID-19 Syndrome.

In this paper we highlight the presence of tachycardia in post-acute COVID-19 syndrome by introducing a new label for this phenomenon-post-COVID-19 tachycardia syndrome-and argue that this constitutes a phenotype or sub-syndrome in post-acute COVID-19 syndrome. We also discuss epidemiology, putative mechanisms, treatment options, and future research directions in this novel clinical syndrome.

COVID-19-induced postural orthostatic tachycardia syndrome treated with ivabradine.

A 22-year-old woman was referred with exertional dyspnoea and chest tightness 3 weeks following a diagnosis of COVID-19. Evaluation revealed a resting sinus tachycardia and criteria for postural orthostatic tachycardia syndrome were met. After non-pharmacological interventions failed to yield symptomatic improvement, ivabradine was commenced. This intervention was followed by a substantial improvement in the patient's exercise tolerance and energy levels and an objective reduction in supine and standing heart rate.

Electrocardiographic findings of methanol toxicity: A cross-sectional study on 356 cases in Iran (preprint)

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.

Uncommon presentation of COVID-19: Gastrointestinal bleeding.

The COVID-19 outbreak has become a pandemic that is threatening global health. The typical clinical manifestations were fever, cough, dyspnea, and myalgia or fatigue. Digestive symptoms such as nausea, vomiting, diarrhea, abdominal pain usually accompany respiratory symptoms. However gastrointestinal bleeding as the first symptom is not reported. Here we reported a case of COVID-19 with gastrointestinal bleeding as the initial symptom to the emergency department with a real-time reverse transcriptase polymerase chain reaction test positive, and normal thorax tomography. The case demonstrate that; clinicians should be alerted to patients about COVID-19 when referring to atypical symptoms and every patient undergoing endoscopy should be considered potentially infected or can infect others.