Cardiac QT Interval Research Articles

Artificial intelligence enabled electrocardiogram for mortality and ventricular arrhythmia prediction

Abstract Background Artificial intelligence-enhanced electrocardiograms (AI-ECG) can be used to predict risk of events but existing models suffer from lack of actionability, explainability and biological plausibility, and therefore are not used clinically. Purpose We sought to address these limitations of previous AI-ECG approaches by developing the AI-ECG risk estimator (AIRE). Methods AIRE was developed in a dataset of 1,163,401 ECGs from 189,539 patients from a secondary care setting in the USA. Uniquely, AIRE uses deep learning with a residual convolutional neural network with a discrete-time survival loss function to create a subject-specific survival curve using a single ECG. AIRE was trained to predict time-to-mortality and fine-tuned for the additional endpoints described below. Results AIRE outputs a subject-specific survival curve that predicts not only mortality but time-to-mortality, using only a single ECG (Figure 1A). AIRE accurately predicts risk of all-cause mortality (C-index 0.775 (0.773-0.776), Figure 2) and can differentiate prognosis in high and low risk subjects even when only cardiologist reported normal ECGs are considered (Figure 2). AIRE also accurately predicted cardiovascular (CV) death 0.832 (0.831-0.834), future ventricular arrhythmia (0.760 (0.756-0.763)), future atherosclerotic cardiovascular disease (0.696 (0.694-0.698)) and future heart failure (0.787 (0.785-0.889))). In particular AIRE was superior to left ventricular ejection fraction (LVEF) in predicting risk of future ventricular arrhythmias in subjects with LVEF <50% (C-index 0.649 (0.638 – 0.660) vs 0.615 (0.603 – 0.626) p < 0.0001 ) and in dilated cardiomyopathy (C-index 0.690 (0.669-0.711) vs 0.608 (0.584 – 0.631), p < 0.0001). We used a variational autoencoder (VAE) to visualise the features most correlated with the mortality predictions. Features of QRS morphology, particularly broader and more left bundle branch block morphologies, inverted and biphasic T waves as well as ST segment changes were associated with high predicted mortality (Figure 1B). We externally validated our findings in four diverse, transnational cohorts from Brazil and the UK including volunteers and primary care subjects (Figure 2), and found AIRE accurately predicted all-cause mortality in all four external cohorts. Through phenome- and genome-wide association studies, we identified candidate biological pathways for the prediction of increased risk, including changes in cardiac structure and function (LV mass, LVEF, LV trabeculation), and genes associated with cardiac structure, QT interval, biological aging and metabolic syndrome (VGLL2, KCNQ1, CCDC91, TBX3). Conclusion AIRE is an explainable, biologically plausible and actionable AI-ECG risk estimation platform that has the potential for use worldwide across a wide range of clinical contexts for short- and long-term risk estimation.Figure 1Figure 2

Case report: NSCLC with pulmonary embolism after treatment with almonertinib

Rationale: Almonertinib is the first independently developed third generation epidermal growth factor receptor tyrosine kinase inhibitors in China. It can be used not only for epidermal growth factor receptor (EGFR) sensitive mutation patients but also for T790M (+) resistant patients, and has better safety and survivability compared to the first and second generation EGFR-TKIs. The previous literature and case studies have reported significant treatment-related adverse reactions in non-small cell lung cancers patients treated with almonertinib, including elevated blood creatine phosphatase, prolonged cardiac QT interval, altered myocardial contractility, interstitial lung disease, eye disease, and hematological events. But there are few individual reports of pulmonary embolism events. Patient concerns: A 55-year-old female with no history of smoking visited a local hospital with mild cough and lower sacrococcygeal pain without obvious cause. Diagnosis: She was diagnosed with right lung adenocarcinoma with multiple bone metastases (T2bN1M1c, stage IVB) after image and histological examination, with EGFR 21 exon L858R sensitive mutation. Interventions: She initially underwent surgical treatment due to the discovery of a sacral tumor, and the pathology of the surgery indicated metastatic lung adenocarcinoma. Genetic testing results showed EGFR 21 exon L858R sensitive mutation. Combined with positron emission tomography/computed tomography imaging results and sacral tumor surgical pathology results, it was considered that the patient had lung adenocarcinoma with multiple bone metastases. Treatment plan: targeted treatment with almonertinib which is the third-generation EGFR-TKIs. After only 1 month of targeted treatment, chest enhanced computed tomography revealed pulmonary embolism imaging, combined with coagulation indicators, considering pulmonary embolism. As the thromboembolic site is located at the end of the pulmonary artery branch and imaging shows that tumor lesions are stable. Consider continuing targeted treatment with almonertinib and adjuvant oral anticoagulant therapy with rivaroxaban for treatment. Outcomes: Two months later, the patient’s condition was followed up and it was found that the imaging manifestations of pulmonary embolism disappeared, but the coagulation indicators remained in a hypercoagulable state. The patient’s treatment plan remained unchanged, and the patient was hospitalized for follow-up every 6 to 8 weeks to closely observe changes in the condition. Lessons: There are many reasons for the occurrence of hypercoagulable blood in tumor patients, and there are very few reports of treatment-related pulmonary embolism events in patients who are treated with almonertinib targeted therapy. It is particularly important to determine whether the hypercoagulable blood in such patients is related to targeted therapy drugs in clinical practice, as this will affect the clinical benefits of patients in epidermal growth factor receptor tyrosine kinase inhibitors treatment and the clinical indicators which need to pay more attention in follow-up observation, to avoid serious pulmonary embolism events and thus affect the patient’s survival status and quality of life.

Managing Drug Interactions With Oral Anticancer Treatments.

The use of oral anticancer treatments is widespread and vital to modern cancer treatment. Novel oral chemotherapy and targeted therapy treatments continue to receive US Food and Drug Administration approval every year, making knowledge of these agents a necessity for practitioners working in oncology. Many oral anticancer agents are prone to drug interactions that can contribute to adverse effects and decrease therapy efficacy. Potential drug-drug interactions include (1) interactions with CYP3A4 inhibitors and inducers, (2) interactions related to gastric acid suppression, (3) interactions related to prolongation of the cardiac QT interval, (4) interactions related to anticoagulant medications, and (5) drug-food and drug-herb interactions. Identifying potential drug interactions and appropriately managing them is key to preventing adverse effects and ensuring maximum efficacy while on oral anticancer therapy. Management of adverse effects increases patient compliance, ensures medication safety, and allows patients to remain on therapy. This article discusses the mechanisms of interactions and types of interacting medications. Specific recommendations are discussed.

Polyester Nanocapsules for Intravenous Delivery of Artemether: Formulation Development, Antimalarial Efficacy, and Cardioprotective Effects In Vivo.

Artemether (ATM) is an effective antimalarial drug that also has a short half-life in the blood. Furthermore, ATM is also cardiotoxic and is associated with pro-arrhythmogenic risks. We aimed to develop a delivery system enabling the prolonged release of ATM into the blood coupled with reduced cardiotoxicity. To achieve this, we prepared polymeric nanocapsules (NCs) from different biodegradable polyesters, namely poly(D,L-lactide) (PLA), poly-ε-caprolactone (PCL), and surface-modified NCs, using a monomethoxi-polyethylene glycol-block-poly(D,L-lactide) (PEG5kDa-PLA45kDa) polymer. Using this approach, we were able to encapsulate high yields of ATM (>85%, 0−4 mg/mL) within the oily core of the NCs. The PCL-NCs exhibited the highest percentage of ATM loading as well as a slow release rate. Atomic force microscopy showed nanometric and spherical particles with a narrow size dispersion. We used the PCL NCs loaded with ATM for biological evaluation following IV administration. As with free-ATM, the ATM-PCL-NCs formulation exhibited potent antimalarial efficacy using either the “Four-day test” protocol (ATM total at the end of the 4 daily doses: 40 and 80 mg/kg) in Swiss mice infected with P. berghei or a single low dose (20 mg/kg) of ATM in mice with higher parasitemia (15%). In healthy rats, IV administration of single doses of free-ATM (40 or 80 mg/kg) prolonged cardiac QT and QTc intervals and induced both bradycardia and hypotension. Repeated IV administration of free-ATM (four IV doses at 20 mg/kg every 12 h for 48 h) also prolonged the QT and QTc intervals but, paradoxically, induced tachycardia and hypertension. Remarkably, the incorporation of ATM in ATM-PCL-NCs reduced all adverse effects. In conclusion, the encapsulation of ATM in biodegradable polyester NCs reduces its cardiovascular toxicity without affecting its antimalarial efficacy.

RBM24 controls cardiac QT interval through CaMKIIδ splicing.

Calcium/calmodulin-dependent kinase II delta (CaMKIIδ) is the predominant cardiac isoform and it is alternatively spliced to generate multiple variants. Variable variants allow for distinct localization and potentially different functions in the heart. Dysregulation of CaMKIIδ splicing has been demonstrated to be involved in the pathogenesis of heart diseases, such as cardiac hypertrophy, arrhythmia, and diastolic dysfunction. However, the mechanisms that regulate CaMKIIδ are incompletely understood. Here, we show that RNA binding motif protein 24 (RBM24) is a key splicing regulator of CaMKIIδ. RBM24 ablation leads to the aberrant shift of CaMKIIδ towards the δ-C isoform, which is known to activate the L-type Ca current. In line with this, we found marked alteration in Ca2+ handling followed by prolongation of the ventricular cardiac action potential and QT interval in RBM24 knockout mice, and these changes could be attenuated by treatment with an inhibitor of CaMKIIδ. Importantly, knockdown of RBM24 in human embryonic stem cell-derived cardiomyocytes showed similar electrophysiological abnormalities, suggesting the important role of RBM24 in the human heart. Thus, our data suggest that RBM24 is a critical regulator of CaMKIIδ to control the cardiac QT interval, highlighting the key role of splicing regulation in cardiac rhythm.

Abstract 14733: Fluid Around a Small Heart- Cardiac Manifestation of Anorexia Nervosa

Background: Anorexia Nervosa (AN) is an eating disorder which is characterized by an abnormally low body weight (BMI<18.5), a distorted perception of weight and an intense fear of gaining weight. It is prevalent in about 0.3 to 1% of the US population. Diverse cardiovascular complications are noted in these patients including decreased cardiac output, left ventricular mass and dimensions; pericardial effusion, bradycardia, hypotension and prolonged QT interval. We report a patient presenting with recurrent chest pain, and was diagnosed to have pericardial effusion secondary to AN. Case Presentation: A 27-year-old female with history of iron deficiency anemia, benign ethnic neutropenia, anorexia nervosa and borderline personality disorder, presented with insidious onset of atypical chest pain in the substernal region. Her BMI at presentation was 18.4, vital signs and systemic examination were normal. EKG showed a prolonged QT interval. She was noted to have normal blood cell counts, metabolic parameters and cardiac enzymes. A limited bedside echocardiography was normal except for the presence of mild pericardial effusion. She was treated with anti-inflammatory agents and discharged. A week later she presented with similar complaints. Management: Repeat cell counts were normal. Electrolytes revealed mild hypokalemia. Her CXR showed evidence of microcardia with a pulmonary artery diameter of 0.40. A repeat echocardiogram showed persistence of mild to moderate pericardial effusion. Etiological evaluation was negative for infections, autoimmune markers, and thyroid abnormalities. There was no evidence of ischemia and no rhythm abnormality. Her symptoms improved with analgesics and reassurance. Conclusion: Eating disorders like AN, have protean cardiovascular manifestations. Atypical chest pain in patients with AN is mostly idiopathic (38%) in the absence of risk factors. Silent pericardial effusion is found in about 22% to 71% of patients with AN. In these patients, factors like low BMI, rapid weight loss, low T3 levels, and IGF-1 levels correlate with pericardial effusion. Most patients show resolution of the effusion, normal cardiac dimensions and QT interval, after weight restoration without further intervention necessary.

Electroacupuncture Ameliorates Acute Myocardial Ischemic Injury and Long QT Interval in Mice through the α 1A-Adrenergic Receptor: Electrophysiological, Morphological, and Molecular Evidence.

Acute myocardial ischemia (AMI) is a condition caused by a decrease in blood flow to the heart that can sometimes predispose to acquired long QT syndrome (LQTS), thereby resulting in sudden cardiac death. Recent evidence indicates that electroacupuncture (EA) can alleviate MI injury, but its specific mechanism remains unclear. This study was aimed at investigating the efficacy of EA, which utilizes α1A-adrenergic receptors (α1A-AR) in alleviating MI injury as well as the resulting LQTS. The AMI model was established by ligating the left anterior descending arteries (LAD) of both the wild-type and α1A gene-knockout mice and treating them with EA for three consecutive days. A PowerLab 16 physiological recorder was used to collect the electrocardiogram (ECG) while the serum creatine kinase isoenzymes (CK-MB), lactate dehydrogenase (LDH), and norepinephrine (NE) levels in myocardial tissue were determined by using the enzyme-linked immunosorbent assay (ELISA) kit. Moreover, TTC staining was used to observe the myocardial ischemic area, while H&E and TUNEL staining determined the pathological morphology of the myocardium. Quantitative real-time PCR (qRT-PCR) was used to detect the α1A mRNA, and Western blot was used to detect the specific proteins, such as α1A, cleaved caspase-3, Gq, PLC, p-PKCα, and p-hERG. Our results showed that EA could effectively reduce elevated ST-segment, shorten the extended QT interval, and reduce the serum myocardial enzyme content and the degree of pathological injury in wild mice with MI. EA can also decrease the expression of α1A-AR, PLC, p-PKCα, and NE content in myocardial tissues of wild mice, while those of p-hERG increased in ischemic myocardial tissue. These findings suggested that α1A-AR is involved in the development of MI as well as LQTS. Additionally, EA treatment improves the cardiac function and ischemic long QT interval and plays an important role in reducing the hERG inhibition through the α1A-AR-mediated Gq/PLC/PKCα pathway and myocardial apoptosis. Hence, it is suggested that α1A-AR might become a potential target for EA in treating AMI treatment of myocardial ischemia injury and acquired long QT intervals caused by MI.

Retracted: Association of QT interval indices with cardiac autonomic neuropathy in diabetic patients

Background. Cardiovascular autonomic neuropathy (CAN) is a severely debilitating yet underdiagnosed condition in patients with diabetes mellitus. The prevalence can range from 2.5% (based on the primary prevention cohort in the Diabetes Control and Complications Trial) to as high as 90% of diabetic patients. Clinical manifestations range from orthostasis to myocardial infarction. The diagnosis is made using multiple autonomic function tests to assess both sympathetic and parasympathetic function. This study was conducted to assess the relationship between Cardiac autonomic neuropathy and QT interval. Material and methods. This was a cross-sectional study conducted in 100 patients attending a tertiary care hospital in India. Deep breathing test, Valsalva ratio, immediate heart rate response to standing 30 : 15, BP rise with sustained hand grip and postural hypotension were evaluated. Scoring was done for cardiac autonomic neuropathy. QT interval and QTc interval were determined and association with CAN was obtained. Results. Out of 100 type 2 diabetic patients, 60% were males and 40% were females. 25 patients having no cardiac autonomic neuropathy and had no prolonged QTc interval. While, 75 patients had QTc prolonged were associated with early and severe CAN cardiac autonomic neuropathy. The prolonged QTc was significantly associated with CAN in diabetic patients when compared without CAN and controls (P < 0.0001). The grading score for CAD showed that 75% cases were having score > 2 were 25% of cases had score < 2. Out of 75 patients 44 were between score 2–4 and 31 were above score 4. A significant association between QTc and Diabetic CAN patients observed when compared non CAN and controls. Conclusions. Diabetic cardiac autonomic neuropathy is associated with increase in prolongation of QTc intervals. Hence, there is need for regular checkup of autonomic nervous system in diabetic patient to prevent further complications.

ASSOCIATION of QT INTERVAL INDICES WITH CARDIAC AUTONOMIC NEUROPATHY IN DIABETIC PATIENTS

Relevance. Cardiovascular autonomic neuropathy (CAN) is a severely debilitating yet underdiagnosed condition in patients with diabetes. The prevalence can range from 2.5% (based on the primary prevention cohort in the Diabetes Control and Complications Trial) to as high as 90% of diabetic patients. Clinical manifestations range from orthostasis to myocardial infarction. The diagnosis is made using multiple autonomic function tests to assess both sympathetic and parasympathetic function. 
 Objective: this study was conducted to assess the relationship between Cardiac autonomic neuropathy and QT interval.
 Methods. Cross sectional study was conducted in 100 patients attending tertiary care hospital. Deep breathing test, Valsalva ratio, immediate heart rate response to standing 30:15, B.P rise with sustained hand grip and postural hypotension. Scoring was done for cardiac autonomic neuropathy. QT interval and QTc interval were determined and association with CAN was obtained.
 Results. Out of 100 type-2 diabetic patients, 60% were males and 40% females. 25 patients having no cardiac autonomic neuropathy and had no prolonged QTc interval. While, 75 patients had QTc prolonged were associated with early and severe CAN cardiac autonomic neuropathy. The prolonged QTc was significantly associated with CAN in diabetic patients when compared without-CAN and controls (P<0001).
 Conclusion. Diabetic cardiac autonomic neuropathy is associated with increase in prolongation of QTc intervals. Hence there is need for regular checkup of autonomic nervous system in diabetic patient to prevent further complications.

161 Biosensor in cardiology. T-care project: a preliminary study on innovative wearable non-invasive telemonitoring system

Abstract The demographic trend evolution and the modification of health needs highlight the requirement for a novel organization of the healthcare system. Telemedicine is a technological tool that allows a knockdown of geographic barriers being useful in the management of remote patient assistance. Telemedicine is roughly applied in different cardiology’s areas, from telemetric to implantable devices (loop recorders) in order to monitor cardiac rate, cardiac rhythm variations, and the onset of arrhythmic events. The aim of the present study is to assess the validity of wearable devices (T-shirt equipped with biosensors and bands with photopletimographic system) in monitoring EKG, cardiac rate, and pulse oximetry. We enrolled 38 patients, 25 of whom admitted to the Cardiology Unit, University of Bari. Main characteristics of the sample are listed in Table 1. The difference between traditional monitoring system and wearable biosensors in not statistically significant as shown in Figure 1; therefore the devices tested in this study show a satisfying level of reliability in monitoring cardiac rate, pulse oximetry, QT interval, QRS complexes, and onset of arrhythmic events. However, alerts produced by arrhythmias different from atrial fibrillation are not completely reliable; moreover, the software and the diagnostic algorithm need to be optimized for motion artefacts. For these reasons, results need to be reproduced on a large cohort of patients.

The Role of METTL3-Mediated N6-Methyladenosine (m6A) of JPH2 mRNA in Cyclophosphamide-Induced Cardiotoxicity.

Cyclophosphamide (CYP)-induced cardiotoxicity is a common side effect of cancer treatment. Although it has received significant attention, the related mechanisms of CYP-induced cardiotoxicity remain largely unknown. In this study, we used cell and animal models to investigate the effect of CYP on cardiomyocytes. Our data demonstrated that CYP-induced a prolonged cardiac QT interval and electromechanical coupling time courses accompanied by JPH2 downregulation. Moreover, N6-methyladenosine (m6A) methylation sequencing and RNA sequencing suggested that CYP induced cardiotoxicity by dysregulating calcium signaling. Importantly, our results demonstrated that CYP induced an increase in the m6A level of JPH2 mRNA by upregulating methyltransferases METTL3, leading to the reduction of JPH2 expression levels, as well as increased field potential duration and action potential duration in cardiomyocytes. Our results revealed a novel mechanism for m6A methylation-dependent regulation of JPH2, which provides new strategies for the treatment and prevention of CYP-induced cardiotoxicity.

Heart damage in patients with cirrhosis of the liver

The review outlines the current understanding of the clinical syndrome of heart disease in patients with liver cirrhosis and the development of cirrhotic cardiomyopathy. Patients with cirrhosis of the liver often notice chest pain, palpitations, complaints of arterial hypotension and rapid fatigue. Echocardiography shows that the left ventricular ejection fraction in cirrhosis is preserved at rest and decreases under stress. In some patients with viral liver cirrhosis, there is a decrease in global myocardial deformation (the presence of latent systolic dysfunction). More pronounced impairment of left ventricular diastolic function is recorded in patients with ascites and patients with ChildPugh class B and C. In patients with ascites, unfavorable left ventricular remodeling, left heart cavities enlargement, dilatation of the pulmonary artery and its branches are more common. There is an increase in pulmonary artery pressure, the development of portopulmonary hypertension and hepatopulmonary syndrome in patients with liver cirrhosis. Тhe development of these syndromes leads to a sharp decrease in the quality of life of patients with relatively preserved liver function and a worsening of the prognosis for orthotopic liver transplantation. Аpproximately half of patients with liver cirrhosis have electrophysiological disorders: prolongation of the QT interval, tachycardia, supraventricular and ventricular extrasystoles. To date, there are no clinical guidelines for the management of cirrhotic cardiomyopathy. If a patient with liver cirrhosis develops clinically significant heart failure, then general principles of management of such patients are necessary. It is necessary to limit the use of angiotensin-converting enzyme inhibitors and cardiac glycosides. The combined use of nonselective beta-blockers and nitrates reduce cardiac output and QT interval. The use of potassium canrenoate, lisinopril helps reverse the development of structural and functional changes in left ventricle. The positive effect of antiviral therapy on cardiac hemodynamics in patients with viral cirrhosis was noted. Liver transplantation is known to be an effective treatment for cirrhotic cardiomyopathy, but this treatment may worsen latent heart failure. Thus, in patients with liver cirrhosis, heart damage occurs with the development of cirrhotic cardiomyopathy, while the mechanisms of the development of myocardial dysfunction are not fully understood. Further studies of the development of the syndrome are required for timely diagnosis and clinical intervention to improve the survival of patients.

Replace Finish It With Begin It.

Replace Finish It With Begin It.

Addition of the Aldose Reductase Inhibitor Benzofuroxane Derivative BF-5m to Prolonged and Moderate Exercise Training Enhanced Protection of the Rat Heart From Type-1 Diabetes.

Moderate exercise training may not be sufficient to exert beneficial effects on the cardiovascular system because of the long-term multifactorial etiology of diabetic complications. The addition of a proper pharmacological tool to the physical exercise should improve the outcomes of the diabetic damage. Here it is shown that 8 weeks exercise training of type 1 diabetic Sprague-Dawley (SD) rats resulted in a significantly increased heart rate, a 14% increase in the left ventricular ejection fraction (LVEF) increased plasma insulin levels and a 13% decrease in plasma glucose with respect to sedentary animals. The training also resulted in a 22% reduction in cardiac QT interval from a diabetic sedentary value of 185 ± 19 ms. Treatment of trained rats with the new antioxidant and NO-releasing aldose reductase 2 inhibitor 5(6)-(benzo[d]thiazol-2-ylmethoxy) benzofuroxane BF-5m, 20 mg/kg/day, added a further and significant (P < 0.01 vs. sedentary) increase of the LVEF up to 38% at 8 week time point. The long QT interval recorded in trained rats was reduced to further 12% by addition to the training of pharmacological treatment with 20 mg/kg/day BF-5m. At this time, the association of the two treatments improved the expression into the cardiac tissue of sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA2) and manganese superoxide dismutase (MnSOD), and reduced the fibrosis.

Predictors of late gadolinium enhancement in hypertrophic cardiomyopathy by electrocardiogram and echocardiography

Objective To explore the predictive value of routine echocardiographic and electrocardiographic parameters in late gadolinium enhancement (LGE) in hypertrophic cardiomyopathy (HCM). Methods The study population consisted of a consecutive series of 95 HCM patients.According to the presence of LGE on cardiac magnetic resonance (CMR), these patients were divided into two groups: HCM patients with LGE (n=71) and HCM patients without LGE (n=24). The parameters of routine echocardiography and electrocardiography were compared between the two groups. ROC and Logistic analysis were made to find the predictors of LGE. Results ①As compared to those without LGE, HCM patients with LGE had higher prevalence of chest pain (P=0.027), β-blocker treatment (P=0.024), increased maximal left ventricular wall thickness (MLVWT) (P<0.000 1), non-sustained ventricular tachycardia (P=0.034), prolonged the rate-corrected cardiac QT interval (QTc) (P=0.011), T-wave inversion (TWI) (P=0.009), but reduced early diastolic mitral annular velocity (e′) (P=0.001). ②Univariate predictors of LGE on CMR were: increased MLVWT, reduced e′, prolonged QTc and more TWI. Only MLVWT (OR=1.23, 95%CI=1.05-1.44, P=0.013) and e′(OR=1.23, 95%CI=0.52-0.96, P=0.028) remained independent after multivariable analysis. Furthermore, the ROC analysis showed that these two parameters had discriminative ability to identify those with LGE. To be specific, HCM patients with MLVWT≥21.5 mm or e′≤5.55 cm/s were more likely to present with LGE. ③The leads number of TWI was positively correlated with percentage of LGE in left ventricular mass (LGE%) (r=0.220, P=0.044), but there was no correlation between location of TWI on ECG and territory of LGE on CMR. Conclusions In HCM patients, MLVWT and e′ are independent predictors of LGE on CMR. Furthermore, although the leads number of TWI is correlated with LGE%, no correlation has been found between location of TWI on ECG and territory of LGE on CMR. Key words: Echocardiography; Cardiomyopathy, hypertrophic; Electrocardiography; Late gadolinium enhancement

LRP5 controls cardiac QT interval by modulating the metabolic homeostasis of L-type calcium channel

BackgroundLow-density lipoprotein receptor-related protein 5 (LRP5) has been intensively studied as a co-receptor for β-catenin-dependent Wnt signaling. Emerging evidences have demonstrated β-catenin-independent functions of LRP5. However, the biological role of LRP5 in the mammalian heart is largely unknown. Methods and resultsConditional cardiac-specific Lrp5 knockout (Lrp5-CKO) mice were generated by crossing Lrp5flox/flox mice with αMHC/MerCreMer mice. Lrp5-CKO mice consistently displayed normal cardiac structure and function. Telemetric electrocardiogram recordings revealed a short QT interval in Lrp5-CKO mice, which was tightly linked to the striking abbreviation of action potential duration (APD) in ventricular myocytes. The analysis of whole-cell currents indicated that a reduction in activity and protein expression of L-type calcium channel (LTCC), rather than other ion channels, contributed to the abnormality in APD. Furthermore, we showed that Lrp5 ablation induced a significant convergence of CaV1.2α1c proteins to the endoplasmic reticulum. Consequently, increased proteasomal degradation of these proteins was observed, which was independent of the Wnt/β-catenin signaling pathway. ConclusionsLRP5 directly modulates the degradation of LTCC to control cardiac QT interval. These findings provide compelling evidence for the potential role of LRPs in cardiac electrophysiology.

Pharmacological Modulation of Long Cardiac QT Interval in Ex Vivo and in Vitro Experimental Models

Pharmacological Modulation of Long Cardiac QT Interval in Ex Vivo and in Vitro Experimental Models

Towards Bridging Translational Gap in Cardiotoxicity Prediction: an Application of Progressive Cardiac Risk Assessment Strategy in TdP Risk Assessment of Moxifloxacin

Drug-induced cardiac arrhythmia, especially occurrence of torsade de pointes (TdP), has been a leading cause of attrition and post-approval re-labeling and withdrawal of many drugs. TdP is a multifactorial event, reflecting more than just drug-induced cardiac ion channel inhibition and QT interval prolongation. This presents a translational gap in extrapolating pre-clinical and clinical cardiac safety assessment to estimate TdP risk reliably, especially when the drug of interest is used in combination with other QT-prolonging drugs for treatment of diseases such as tuberculosis. A multi-scale mechanistic modeling framework consisting of physiologically based pharmacokinetics (PBPK) simulations of clinically relevant drug exposures combined with Quantitative Systems Toxicology (QST) models of cardiac electro-physiology could bridge this gap. We illustrate this PBPK-QST approach in cardiac risk assessment as exemplified by moxifloxacin, an anti-tuberculosis drug with abundant clinical cardiac safety data. PBPK simulations of moxifloxacin concentrations (systemic circulation and estimated in heart tissue) were linked with in vitro measurements of cardiac ion channel inhibition to predict the magnitude of QT prolongation in healthy individuals. Predictions closely reproduced the clinically observed QT interval prolongation, but no arrhythmia was observed, even at ×10 exposure. However, the same exposure levels in presence of physiological risk factors, e.g., hypokalemia and tachycardia, led to arrhythmic event in simulations, consistent with reported moxifloxacin-related TdP events. Application of a progressive PBPK-QST cardiac risk assessment paradigm starting in early development could guide drug development decisions and later define a clinical “safe space” for post-approval risk management to identify high-risk clinical scenarios.

Positional cloning of quantitative trait nucleotides for blood pressure and cardiac QT-interval by targeted CRISPR/Cas9 editing of a novel long non-coding RNA.

Multiple GWAS studies have reported strong association of cardiac QT-interval to a region on HSA17. Interestingly, a rat locus homologous to this region is also linked to QT-intervals. The high resolution positional mapping study located the rat QT-interval locus to a <42.5kb region on RNO10. This region contained no variants in protein-coding sequences, but a prominent contiguous 19bp indel polymorphism was noted within a novel predicted long non-coding RNA (lncRNA), which we named as Rffl-lnc1. To assess the candidacy of this novel lncRNA on QT-interval, targeted CRISPR/Cas9 based genome-engineering approaches were applied on the rat strains used to map this locus. Targeted disruption of the rat Rffl-lnc1 locus caused aberrant, short QT-intervals and elevated blood pressure. Further, to specifically examine the significance of the 19bp polymorphism within the Rffl-lnc1 locus, a CRISPR/Cas9 based targeted knock-in rescue model was constructed by inserting the 19bp into the strain which contained the deletion polymorphism. The knock-in alleles successfully rescued the aberrant QT-interval and blood pressure phenotypes. Further studies revealed that the 19bp polymorphism was necessary and sufficient to recapitulate the phenotypic effect of the previously mapped <42.5kb rat locus. To our knowledge, this study is the first demonstration of a combination of both CRISPR/Cas9 based targeted disruption as well as CRISPR/Cas9 based targeted knock-in rescue approaches applied for a mammalian positional cloning study, which defines the quantitative trait nucleotides (QTNs) within a rat long non-coding RNA as being important for the pleiotropic regulation of both cardiac QT-intervals and blood pressure.

Determinants of retinal microvascular features and their relationships in two European populations.

To examine factors influencing retinal vasculature in two environmentally contrasted, cross-sectional studies of adult participants of European descent and to estimate the extent and specificity of genetic contributions to each retinal vasculature feature. Retinal images from 1088 participants in the Orkney Complex Disease Study and 387 in the CROATIA-Korčula study, taken using the same nonmydriatic camera system and graded by the same person, were evaluated. Using general linear models, we estimated the influence of an extensive range of systemic risk factors, calculated retinal traits heritabilities and genetic correlations. Systemic covariates explained little (<4%) of the variation in vessel tortuosity, substantially more (>10%, up to 31.7%) of the variation in vessel width and monofractal dimension. Suggestive not well trodden associations of biological interest included that of urate, tissue plasminogen activator and cardiac PR interval with arteriolar narrowing, that of carotid intima-media thickness with less-tortuous arterioles and of cardiac QT interval with more tortuous venules. The genetic underpinning of tortuosity is largely distinct from that of the other retinal vascular features, whereas that of fractal dimension and vessel width greatly overlaps. The previously recognized influence of ocular axial length on vessel widths was high and can be expected to lead to artefactual genetic associations [genetic correlation with central retinal arteriolar equivalent: -0.53 (standard error 0.11)]. The significant genetic correlation between SBP and central retinal arteriolar equivalent, -0.53 (standard error 0.22) (after adjusting for age, sex and axial length of the eye), augurs more favourably for the discovery of genetic variants relevant to vascular physiology.