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Background Since its discovery in Wuhan, China in December of 2019, the novel coronavirus has progressed to become one of the worst pandemics seen in the last 100 years. Recently, there has been an increased interest in the hepatic manifestations of coronavirus disease 19 (COVID-19). Aim To describe the demographic and clinical characteristics of COVID-19 positive patients and study the association between transaminitis and all-cause mortality. Methods This is a descriptive retrospective cohort study of 130 consecutive patients with a positive COVID PCR test admitted between March 16, 2020 to May 14, 2020 at a tertiary care University-based medical center. The Wilcoxon-rank sum test and paired t-test were used for comparing non-parametric and parametric continuous variables respectively and a multivariable logistic regression models to study the association between transaminitis and mortality using SAS version 9.4 (SAS Institute, Cary, NC, United States). Results Out of the 130 patients, 73 (56%) patients were found to have transaminitis and 57 (44%) did not. When compared to patients without transaminitis, the transaminitis group was found to have a higher median body mass index (30.2 kg/m2 vs 27.3 kg/m2, P = 0.04). In the multivariate analysis those with transaminitis were found to have 3.4 times higher odds of dying as compared to those without transaminitis adjusting for gender, the Age-adjusted Charlson Comorbidity Index and admission to the intensive care unit (P = 0.03). Conclusion Our study showed that transaminitis on admission was associated with severe clinical outcomes such as admission to the intensive care unit, need for mechanical ventilation, and mortality.

A 47-year-old female with attention-deficit/hyperactivity disorder on prescription Adderall presented to the hospital with worsening dyspnea for the one-month duration. She was admitted to the medical intensive care unit with respiratory failure requiring non-invasive positive pressure ventilation. Cardiac catheterization confirmed the diagnosis of non-cardiogenic pulmonary edema. With the discontinuation of Adderall, use of BiPAP, and aggressive diuresis with loop diuretics, there was evidence of symptomatic, laboratory, and radiological improvement. Her symptoms were attributed to Adderall use as a diagnosis of exclusion. To our knowledge, this paper reports the first case of Adderall-induced non-cardiogenic pulmonary edema leading to respiratory failure. Although case reports of abuse or overdose of other stimulants such as amphetamine and cocaine leading to a plethora of cardiac and pulmonary complications such as acute respiratory distress syndrome (ARDS), cardiogenic pulmonary edema, and non-cardiogenic pulmonary edema exist, there are no reports that using Adderall at routine prescription doses can lead to these problems.

Effective communication is key to patient satisfaction. Family meetings been shown to be effective in other settings such as critical care and palliative medicine. We evaluated the impact of scheduled and structured family meetings on patients admitted to the hospitalist service in terms of satisfaction with care delivery. More patients in the intervention group reported better understanding of their diagnosis, treatment plan, medications, and discharge plan. Based on these results, we advocate for structured and scheduled family meetings to be implemented as a communication tool for selected patients on the hospital medicine service to improve patient experience and satisfaction.

A 69-year-old man without a family history of breast cancer presented to his primary care physician with a 1-year history of clear, unilateral nipple discharge (ND) without an associated palpable breast mass. His laboratory findings were significant for hyperprolactinaemia at 28 ng/mL. Diagnostic work up including mammography, ultrasound and core needle biopsy ultimately revealed a ductal carcinoma in situ and a rare papillary variant of invasive ductal carcinoma. The patient was referred to a multidisciplinary oncology team and underwent a right total mastectomy followed by adjuvant hormonal therapy. The patient made a good postoperative recovery and remains without evidence of recurrence 6 months from surgery. Male breast cancer is rare, but its incidence is increasing. Male breast cancer presenting as ND without a palpable mass is uncommon. Early recognition of breast symptoms in men can lead to earlier diagnoses and improved outcomes.

Background and Purpose Prior studies examining sex-related risk of readmission for ischemic stroke (IS) after coronary artery bypass grafting (CABG) did not adjust for preoperative comorbidities and used small study samples that were single-center or otherwise poorly generalizable. We assessed risk of readmission for IS after CABG for females compared to males in a nationwide sample. Methods The 2013 Nationwide Readmissions Database contains data on 49% of all U.S. hospitalizations. We used population weighting to determine national estimates. Using all follow-up data up to 1 year after discharge from CABG hospitalization, we estimated Kaplan-Meier cumulative risk of IS, stratified by sex, using the log-rank test for significance. We created Cox proportional hazard models to calculate hazard ratios (HR) and 95% confidence intervals (CI) for IS readmission, with sex as the main independent variable. We ran unadjusted models and models adjusted for age, vascular risk factors, estimated severity of illness and risk of mortality, hospital characteristics, and income quartile of patient's zip code. Results An estimated 53,270 females and 147,396 males survived index CABG admission in 2013. There was a consistently elevated cumulative risk of readmission for IS after CABG for females versus males (log-rank p-value = 0.0014). In the unadjusted Cox model, the HR of IS in females vs. males was 1.35 (95% CI 1.12–1.62, p = 0.0015). The elevated risk for females remained after adjusting for severity of illness (1.30 [1.08–1.56], p = 0.0056) and risk of mortality (1.28 [1.07–1.54], p = 0.0086). This elevated risk persisted after adjusting for multiple vascular risk factors, hospital characteristics, and income quartile of patient's zip code (1.23 [1.02–1.48], p = 0.03). Conclusions We found a 23% increased risk of readmission for IS up to 1 year after CABG for females compared to males in a fully adjusted model utilizing a large, contemporary, nationwide database. Further research would clarify mechanisms of this increased risk among women.

The objective of this study was to improve the quality of chest compressions after the introduction of a metronome during cardiopulmonary resuscitation (CPR). A retrospective analysis of Zoll(®) compression data of 219 in-hospital adult participants who received CPR from January 2017 to December 2018 was done. A metronome was introduced during chest compressions in January 2018, and the 2017 data served as the control. The main outcome measure compared the overall quality of chest compressions measured by the rate (100 to 120 compressions per minute), depth (2.0 to 2.4 inches), and mean release velocity (≥400 mm/sec) on chest recoil. Compared to control, the metronome group had a statistically significant improvement of the mean percent compression rate within 100 to 120 beats per minute: 28.16% vs. 71.14% (P < 0.001) and a statistically significant improvement of the mean percent compression depth within 2.0 to 2.4 inches: 29.35% vs. 34.84% (P = 0.03). However, there was no statistically significant improvement of mean percent release velocity ≥400 mm/second: 47.41% vs. 51.09% (P = 0.38). Our data suggest that an inexpensive and widely available intervention may improve the quality of CPR. We suggest that further research be conducted to measure patient clinical outcomes.

A 66-year-old woman presented to the hospital with a one-month history of shortness of breath, fatigue, and postmenopausal vaginal bleeding and a one-week history of chest pain. This case report discusses the rare synchronous occurrence of two different malignancies in the setting of non-ST segment elevation myocardial infarction and the relation between these unfortunate events. Besides the case presented in this report, there have been only 13 reported cases of synchronous chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) associated with metastatic squamous cell carcinoma. While it is well known that malignancy causes a hypercoagulable state, there are other mechanisms which may have contributed to the patient’s myocardial ischemia including external vascular compression, tumor lysis syndrome, and anemia. This case report discusses the rarity of synchronous malignancies but the importance of understanding and consideration of cardiac events in this population.

Introduction: Prior studies examining sex-related risk of readmission for ischemic stroke after coronary artery bypass grafting (CABG) did not adjust for preoperative co-morbidities and used small study samples that were single center or otherwise poorly generalizable. We assessed risk of readmission for ischemic stroke after CABG for females compared to males in a nationwide sample. Methods: The 2013 Nationwide Readmissions Database contains data on nearly 60% of all U.S. hospitalizations. We used population weighting to determine national estimates. Using all follow-up data up to 1 year after discharge from CABG hospitalization, we estimated Kaplan-Meier cumulative risk of ischemic stroke, stratified by sex, using the log-rank test for significance. We created Cox proportional hazard models to calculate hazard ratios (HR) and 95% confidence intervals (CI) for ischemic stroke readmission, with sex as the main independent variable. We ran unadjusted models and models adjusted for age, vascular risk factors, estimated severity of illness and risk of mortality, hospital characteristics, and income quartile of patient’s zip code. Results: An estimated 53,270 females and 147,396 males survived index CABG admission in 2013. There was a consistently elevated cumulative risk of readmission for ischemic stroke after CABG for females versus males (log-rank p value=0.0014). In the unadjusted Cox model, the HR of ischemic stroke in females vs. males was 1.35 (95% CI 1.12-1.62, p=0.0015). The elevated risk for females remained after adjusting for severity of illness (1.30 [1.08-1.56], p=0.0056) and risk of mortality (1.28 [1.07-1.54], p=0.0086). This elevated risk persisted after adjusting for multiple vascular risk factors, hospital characteristics, and income quartile of patient’s zip code (1.23 [1.02-1.48], p=0.03). Conclusions: In conclusion, we found a 23% increased risk of readmission for ischemic stroke up to 1 year after CABG for females compared to males in a fully adjusted model utilizing a large, contemporary, nationwide database. Further research would clarify mechanisms of this increased risk among women.

With increased oversight of residency work hours, there has been an increase in shift handoffs, which are prone to medical errors. To date, there are no evidence-based recommendations on essential elements of shift handoffs. We implemented a standardized shift-handoff rubric at an academic medicine residency program. Compliance, resident/faculty perceptions, and surrogate markers of patient safety were measured. Shift-handoff documents were collected January-February 2016 (control) April-June 2016 (intervention). Signouts were scored based on inclusion of seven elements: Daily events, Overnight events, Code status, Follow up tasks, If/then statements, ‘sick or stable’ and History present illness. The mnemonic ‘DOCFISH’ was taught in a grand-rounds forum then embedded into a shift-handoff tool within our electronic health record (EHR). Senior residents were assigned to supervise/provide feedback on shift handoffs from April-June 2016. Faculty and resident perceptions regarding quality of shift handoffs was measured by the annual ACGME (Accreditation Council Graduate Medical Education) program survey. Patient safety was measured by number of rapid-response teams (RRT) initiated for unstable vital signs. Handoffs were 74% complete in intervention group and 60% in control group (p

Dear Editor,Turmeric has a long history of medicinal use and is thought to have therapeutic properties including liver protective effects and anti-oxidant properties. More recently, there has been ...

Adenovirus is a family of double stranded DNA viruses that are a significant cause of upper respiratory tract infections in children and adults. Less commonly, the adenovirus family can cause a variety of gastrointestinal, ophthalmologic, genitourinary, and neurologic diseases. Most adenovirus infections are self-limited in the immunocompetent host and are treated with supportive measures. Fatal infections can occur in immunocompromised patients and less frequently in the healthy. Adenoviral vectors are being studied for novel biomedical applications including gene therapy and immunization. In this review we will focus on the spectrum of adenoviral infections in humans.

Angiosarcoma is a cancer that is derived from endothelial cells that line blood vessels and lymphatic channels. Cutaneous angiosarcoma can appear anywhere on the skin and the clinical presentation is highly variable. Most cases appear on the scalp and face de novo. Our case describes a 91-year-old female with cutaneous scalp angiosarcoma. Our case serves to remind physicians that an abnormal skin finding in older adults should raise their index of suspicion for angiosarcoma and an early biopsy should be performed.

A 26-year-old female from India presented with progressive, unremitting low back pain for over 1 year. She had been treated unsuccessfully for left-sided sacroiliitis, pelvic floor dysfunction, ankylosing spondylitis and seronegative spondyloarthritis. MRI lumbar spine showed a Schmorl node with surrounding marrow oedema at L4, the relevance of which is not clear in literature. One year after initial presentation, a biopsy of this lesion revealed culture positive diagnosis of spinal tuberculosis. Despite advances in imaging, delayed diagnosis is not uncommon in spinal tuberculosis (TB). In our case, it was also attributed to an unknown early lesion: Schmorl node with surrounding oedema. Any association of this lesion with spinal TB has previously not been reported.

ObjectivesTo design a tool to assess and improve physician communication, provide physicians with personalised feedback in real time, and relate specific communication behaviours to patient experience measures. It was hypothesised that performance of fundamental communication behaviours would correlate with individual patient experience scores as measured by the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) surveys.DesignProspective observational study.SettingSingle-centre study at a mid-sized academic tertiary medical centre.ParticipantsThirteen hospitalists across 305 patient interactions were assessed in this study. Participants were recruited from three geographically cohorted adult general medicine-teaching teams on two inpatient units. Participants with cognitive impairment or who were unable to speak English were excluded from the study.Main outcome measuresFrequency of performance of 10 fundamental communication behaviours.ResultsThe communication behaviours of 13 hospitalists were assessed by 305 surveys: 146 observations, 106 patient reports and 52 excluded interactions. During rounds, 50% of physicians introduced themselves, 40% explained their role, 44% introduced other members of the team, 59% addressed patients by name, 58% addressed friends/family, 59% attempted to be at eye level, 41% asked permission before performing a physical examination, 40% asked if patients had questions and 20% asked if patients understood the plan of care. Several variables correlated with higher HCAHPS scores; however, addressing patients by name (r=0.60482, p=0.0492) and introducing other members of the team (r=0.87239, p=0.0234) were statistically significant.ConclusionThis study highlights the importance of effective physician–patient communication and presents a unique data collection tool to assess and improve physician communication in real time. This tool can provide physicians with personalised feedback and relate specific communication behaviours to patient experience measures to provide high-quality care and improve the patient experience.

Sinonasal neuroendocrine tumours (NETs) are rare, aggressive neoplasms with a high recurrence potential. There are no robust protocols for the management of these tumours. An 81-year-old man presented with an incidental sinonasal mass visualised on CT scan of head. Over the next few weeks he developed new onset, progressively worsening headache, right eye ptosis and restricted extraocular movements. Imaging confirmed a rapidly enlarging tumour involving the right nasal cavity and the orbit. Biopsy showed a large cell neuroendocrine carcinoma of the right ethmoidal sinus. The patient was treated with concurrent cisplatin chemotherapy and radiation. Repeat imaging showed decrease in tumour volume. The patient continues to do well and follows up regularly with our oncology service. Current protocols comprising chemotherapy after radiation are based on limited studies. A regimen involving concurrent chemoradiation also appears to aid in tumour volume reduction. Additional studies are required to formulate robust clinical protocols for management of sinonasal NETs.

Background Mental health disease is under recognized in medical professionals. Objective To screen medical students (MS), residents and fellows for major depressive disorder (MDD) and generalized anxiety disorder (GAD) under the new era of work hour reform with age-matched controls from a large representative cross-sectional survey. Methods We conducted an anonymous online survey at a medical university in 2013–2014. We incorporated the Patient Health Questionnaire 2 (PHQ-2) to screen for MDD and the generalized anxiety disorder scale (GAD-7) to screen for GAD, along with additional questions on life stressors and academic performance. We compared these results to age-matched controls from the National Health and Nutrition Examination Survey (NHANES) database. Results 126 residents/fellows and 336 medical students participated voluntarily. 15.1% and 15.9% of postgraduates as well as 16.4% and 20.3% of MS screened positive for MDD and GAD, respectively. When compared to national estimates, the prevalence of a positive screen for MDD was over five-fold higher in medical trainees compared to age-matched controls (16% vs. 2.8%, p

Learning points for clinicians Non-selective beta-blockers, avoidance of high-salt, carbohydrate-rich meals and strenuous exertion are essential in acute management, until thyrotoxicosis is treated. Unlike primary, or familial, hypokalemic periodic paralysis, potassium supplementation alone is ineffective.1 Acetazolamide and T4 supplementation may precipitate or worsen paralysis in thyrotoxic periodic paralysis.1 Thyrotoxic periodic paralysis (TPP) is a rare disease entity that is often overlooked. The disease is an easily treatable entity but, if missed, can be debilitating and life threatening. We present a case where a young healthy male was admitted to our Critical Care Unit with suspicion of stroke. Upon further work up, he was diagnosed with profound hypokalemia and hyperthyroidism. His symptoms were finally attributed to TPP; which completely resolved following treatment. A 27-year-old Asian male came into …

There has been a significant evolution in the definition and management of sepsis over the last three decades. This is driven in part due to the advances made in our understanding of its pathophysiology. There is evidence to show that the manifestations of sepsis can no longer be attributed only to the infectious agent and the immune response it engenders, but also to significant alterations in coagulation, immunosuppression, and organ dysfunction. A revolutionary change in the way we manage sepsis has been the adoption of early goal-directed therapy. This involves the early identification of at-risk patients and prompt treatment with antibiotics, hemodynamic optimization, and appropriate supportive care. This has contributed significantly to the overall improved outcomes with sepsis. Investigation into clinically relevant biomarkers of sepsis are ongoing and have yet to yield effective results. Scoring systems such as the sequential organ failure assessment and Acute Physiology and Chronic Health Evaluation help risk-stratify patients with sepsis. Advances in precision medicine techniques and the development of targeted therapy directed at limiting the excesses of the inflammatory and coagulatory cascades offer potentially viable avenues for future research. This review summarizes the progress made in the diagnosis and management of sepsis over the past two decades and examines promising avenues for future research.

The complementary fields of genomics and proteomics offer insights into the molecular mechanisms of diseases. While genomics seeks to define our genetic substrate, proteomics explores the structure and function of proteins, which are the end effectors of our genes. Proteomics has been revolutionized in the past decade by the application of techniques such as protein arrays, two-dimensional gel electrophoresis, and mass spectrometry. These techniques have tremendous potential for biomarker development, target validation, diagnosis, prognosis, and optimization of treatment in medical care, especially in the field of clinical oncology. We will discuss innovations in proteomic technologies and highlight their prospective applications to patient care.

Background Data on pH regulation of the cardiac potassium current I K1 suggest species-dependent differences in the molecular composition of the underlying Kir2 channel proteins. Objective The purpose of this study was to test the hypothesis that the presence of the Kir2.3 isoform in heterotetrameric channels modifies channel sensitivity to pH. Methods Voltage clamp was performed on HEK293 cells stably expressing guinea pig Kir2.1 and/or Kir2.3 isoforms and on sheep cardiac ventricular myocytes at varying extracellular pH (pH o ) and in the presence of CO 2 to determine the sensitivity of macroscopic currents to pH. Single-channel activity was recorded from the HEK293 stables to determine the mechanisms of the changes in whole cell current. Results Biophysical characteristics of whole-cell and single-channel currents in Kir2.1/Kir2.3 double stables displayed properties attributable to isoform heteromerization. Whole-cell Kir2.1/Kir2.3 currents rectified in a manner reminiscent of Kir2.1 but were significantly inhibited by extracellular acidification in the physiologic range (p K a ∼ 7.4). Whole-cell currents were more sensitive to a combined extracellular and intracellular acidification produced by CO 2 . At pH o = 6.0, unitary conductances of heteromeric channels were reduced. Ovine cardiac ventricular cell I K1 was pH o and CO 2 sensitive, consistent with the expression of Kir2.1 and Kir2.3 in this species. Conclusion Kir2.1 and Kir2.3 isoforms form heteromeric channels in HEK293. The presence of Kir2.3 subunit(s) in heteromeric channels confers pH sensitivity to the channels. The single and double stable cells presented in this study are useful models for studying physiologic regulation of heteromeric Kir2 channels in mammalian cells.

Novel technologies are now being advanced for the purpose of identification and validation of new disease biomarkers. A reliable and useful clinical biomarker must a) come from a readily attainable source, such as blood or urine, b) have sufficient sensitivity to correctly identify affected individuals, c) have sufficient specificity to avoid incorrect labeling of unaffected persons, and d) result in a notable benefit for the patient through intervention, such as survival or life quality improvement. Despite these critical descriptors, the few available FDA-approved biomarkers for cancer do not completely fit this definition and their benefits are limited to a small number of cancers. Ovarian cancer exemplifies the need for a diagnostic biomarker of early stage disease. Symptoms are present but not specific to the disease, delaying diagnosis until an advanced and generally incurable stage in over 70% of affected women. As such, diagnostic intervention in the form of oopherectomy can be performed in the appropriate at-risk population if identified such as with a new accurate, sensitive, and specific biomarker. If early stage disease is identified, the requirement for survival and life quality improvement will be met. One of the new technologies applied to biomarker discovery is tour-de-force analysis of serum peptides and proteins. Optimization of mass spectrometry techniques coupled with advanced bioinformatics approaches has yielded informative biomarker signatures discriminating presence of cancer from unaffected in multiple studies from different groups. Validation and randomized outcome studies are needed to determine the true value of these new biomarkers in early diagnosis, and improved survival and quality of life.

The cardiac inwardly rectifying potassium current (I(K1)) stabilizes the resting membrane potential and is responsible for shaping the initial depolarization and final repolarization of the action potential. The inwardly rectifying potassium channel (Kir2.x) subfamily members primarily mediate cardiac I(K1), but other inward rectifiers, including the acetylcholine-sensitive (Kir3.x) and ATP-sensitive (Kir6.x) inward rectifiers, also may modulate cardiac excitability. Studies suggest I(K1) plays a role in ventricular arrhythmias, highlighted by the recently described Andersen's syndrome and studies in the guinea pig heart model of ventricular fibrillation. This article describes the salient properties of cardiac I(K1) and discusses the role of this current in the cardiac action potential and in underlying regional differences in cardiac excitability. The mechanism of channel block, assembly, and structure are reviewed. The article discusses the role of I(K1) in ventricular fibrillation and speculates on modulation of I(K1) as a preventative antiarrhythmic mechanism.

A spinal epidural abscess is the collection of pus in the epidural space, and is a potentially life-threatening condition that requires early detection and prompt management. Almost two-thirds of cases are caused by Staphylococcus aureus, followed by Gram-negative bacilli which account for approximately 16% of cases. Raoultella planticola is an emerging pathogen, and is an extremely rare cause of invasive infection in humans. It has been reported to cause urinary tract infections, pneumonia, bacteraemia, cholangitis, cholecystitis, conjunctivitis and soft tissue infections. We report the first case, to our knowledge, of R. planticola osteomyelitis and spinal epidural abscess.

Acutely decompensated heart failure (HF), one of the most common reasons for hospitalization, places an intense economic pressure on the health care system and adversely affects outcome of HF patients. Due to lack of reliable clinical tools to assess and monitor hemodynamics, accurate judgment on cardiac preload remains a challenge and complicates current inpatient HF management. In this review, we discuss the emerging role of real-time quantitative Doppler echocardiography (DE) in identifying inappropriate cardiac preload, monitoring volume status during the management, and improving quality of care in patients with acute HF. We illustrate the utilization of DE in common clinical scenarios, propose stepwise algorithms to effectively utilize serial quantitative DE in the bedside care, and discuss obstacles and prospects of quantitative DE utilization in HF management. These efforts will further prompt the development of multi-center prospective studies to define and validate the specific roles of quantitative DE in reducing hospitalization time and improving outcome of HF patients.

Teratomas are embryonal neoplasms which arise from totipotential cells and contain elements from all three germ layers (ectoderm, mesoderm, and the endoderm). Simultaneous occurrence of mediastinal and gastric teratomas in infants has not been reported, although gastric teratomas extending into the mediastinum have been reported twice in literature. We report here a case in which a gastric cystic teratoma was connected to its mediastinal counterpart with a pedicle. The pertinent literature is reviewed.

We read with great interest the report by Kociol et al. [(1)][1] on the association between inpatient hospitalist care of patients with heart failure and clinical outcomes. Their results suggest that utilization of the hospitalist model for patient care did not improve 30-day outcomes. Although

Objective To examine prevalence rates of psychopathology in children with velocardiofacial syndrome (VCFS). Method One hundred fifty-four children ages 6 to 15 participated in our between-group design with three samples, 84 children with VCFS (37 girls, 47 boys), 32 sibling controls (18 girls, 14 boys), and 38 community controls (12 girls, 26 boys). The Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version and several other parent report measures were used to assess for psychopathology. Results Compared to both control samples, children with VCFS had higher prevalence rates of major depressive disorder, attention-deficit/hyperactivity disorder, simple phobias, and enuresis. Additional findings from our analyses include (1) no gender differences in VCFS psychopathology prevalence rates, (2) children with VCFS who have comorbid psychopathology were rated by their parents as having less well-developed executive functions, and (3) across all three samples, the higher the IQ was, the higher the level of global functioning. Conclusions These findings are consistent with previous research and suggest that major depressive disorder, attention-deficit/hyperactivity disorder, and simple phobias are salient features of the VCFS psychiatric phenotype.

Short QT syndrome (SQTS) leads to an abbreviated QTc interval and predisposes patients to life-threatening arrhythmias. To date, two forms of the disease have been identified: SQT1, caused by a gain of function substitution in the HERG ( I Kr ) channel, and SQT2, caused by a gain of function substitution in the KvLQT1 ( I Ks ) channel. Here we identify a new variant, “SQT3”, which has a unique ECG phenotype characterized by asymmetrical T waves, and a defect in the gene coding for the inwardly rectifying Kir2.1 ( I K1 ) channel. The affected members of a single family had a G514A substitution in the KCNJ2 gene that resulted in a change from aspartic acid to asparagine at position 172 (D172N). Whole-cell patch-clamp studies of the heterologously expressed human D172N channel demonstrated a larger outward I K1 than the wild-type ( P I K1 greatly accelerated the final phase of repolarization, and shortened the action potential duration. Hence, unlike the known mutations in the two other SQTS forms (N588K in HERG and V307L in KvLQT1), simulations using the D172N and WT/D172N mutations fully accounted for the ECG phenotype of tall and asymmetrically shaped T waves. Although we were unable to test for inducibility of arrhythmia susceptibility due to lack of patients’ consent, our computer simulations predict a steeper steady-state restitution curve for the D172N and WT/D172N mutation, compared with WT or to HERG or KvLQT1 mutations, which may predispose SQT3 patients to a greater risk of reentrant arrhythmias.

The inwardly rectifying potassium (Kir) 2.x channels mediate the cardiac inward rectifier potassium current (I K1 ). In addition to differences in current density, atrial and ventricular I K1 have differences in outward current profiles and in extracellular potassium ([K + ] o ) dependence. The whole-cell patch-clamp technique was used to study these properties in heterologously expressed Kir2.x channels and atrial and ventricular I K1 in guinea pig and sheep hearts. Kir2.x channels showed distinct rectification profiles: Kir2.1 and Kir2.2 rectified completely at potentials more depolarized than −30 mV (I≈0 pA). In contrast, rectification was incomplete for Kir2.3 channels. In guinea pig atria, which expressed mainly Kir2.1, I K1 rectified completely. In sheep atria, which predominantly expressed Kir2.3 channels, I K1 did not rectify completely. Single-channel analysis of sheep Kir2.3 channels showed a mean unitary conductance of 13.1±0.1 pS in 15 cells, which corresponded with I K1 in sheep atria (9.9±0.1 pS in 32 cells). Outward Kir2.1 currents were increased in 10 mmol/L [K + ] o , whereas Kir2.3 currents did not increase. Correspondingly, guinea pig (but not sheep) atrial I K1 showed an increase in outward currents in 10 mmol/L [K + ] o . Although the ventricles of both species expressed Kir2.1 and Kir2.3, outward I K1 currents rectified completely and increased in high [K + ] o -displaying Kir2.1-like properties. Likewise, outward current properties of heterologously expressed Kir2.1-Kir2.3 complexes in normal and 10 mmol/L [K + ] o were similar to Kir2.1 but not Kir2.3. Thus, unique properties of individual Kir2.x isoforms, as well as heteromeric Kir2.x complexes, determine regional and species differences of I K1 in the heart.

Objective: We tested the hypothesis that left atrial (LA) myocytes are more sensitive to acetylcholine (ACh) than right atrial (RA) myocytes, which results in a greater dose-dependent increase in LA than RA rotor frequency, increased LA-to-RA frequency gradient and increased incidence of wavelet formation during atrial fibrillation (AF). Methods and results: AF was induced in seven Langendorff-perfused sheep hearts in the presence of ACh (0.1–4.0 μM) and studied using optical mapping and bipolar recordings. Dominant frequencies (DFs) were determined in optical and electrical signals and phase movies were used to identify rotors and quantify their dynamics. DFs in both atria increased monotonically with ACh concentration until saturation, but the LA frequency predominated at all concentrations. Rotors were also seen more often in the LA, and although their life span decreased, their frequency and number of rotations increased. Patch-clamp studies demonstrated that ACh-activated potassium current ( I K,ACh) density was greater in LA than RA sheep myocytes. Additionally, ribonuclease protection assay demonstrated that Kir3.4 and Kir3.1 mRNAs were more abundant in LA than in RA. Conclusions: A greater abundance of Kir3. x channels and higher I K,ACh density in LA than RA myocytes result in greater ACh-induced speeding-up of rotors in the LA than in the RA, which explains the ACh dose-dependent changes in overall AF frequency and wavelet formation.

Cardiac fibrillation is a major health problem in industrialized society today. In the United States alone, ventricular fibrillation (VF) is responsible for approximately 300,000 sudden cardiac deaths (Myerburg,Catellanos,1997). On the other hand, atrial fibrillation (AF) afflicts over 2 million Americans, (Feinberg et a1,1995) which makes it the most prevalent cardiac arrhythmia in clinical practice. While AF in and of itself does not usually lead to death, it is the most important cause of stroke. (Wolf et a1,1991). Because of the alarming nature of these statistics, understanding the mechanisms underlying fibrillation of the heart is very critical.