Methadone Blockade of Cardiac Inward Rectifier K Current Augments Membrane Instability and Amplifies U Waves on Surface ECGs: A Translational Study.

Background Methadone is associated with a disproportionate risk of sudden death and ventricular tachyarrhythmia despite only modest inhibition of delayed rectifier K current () the principal mechanism of drug-associated arrhythmia. Congenital defects of inward rectifier K current () have been linked to increased U-wave amplitude on ECG and fatal arrhythmia. We hypothesized that methadone may also be a potent inhibitor of , contributing to delayed repolarization and manifesting on surface ECGs as augmented U-wave integrals.

Q Fever and Kingella kingae Endocarditis in a Toddler: A Rare Coinfection Case.

A toddler after tetralogy of Fallot graft repair in infancy was diagnosed with endocarditis. Blood cultures were positive for Kingella kingae and serology was positive Coxiella burnetii. He was treated medically and surgically.

Hemodynamic Effects of Late Sodium Current Inhibitors in a Swine Model of Heart Failure.

Objectives: To evaluate possible treatment-related hemodynamic changes, we administered ranolazine or mexiletine to swine with heart failure (HF) and to controls.

Background: Ranolazine and mexiletine potently inhibit depolarizing late Na current (I) and Na entry into cardiomyocytes Blocking Na entry may increase forward-mode Na/Ca exchange and reduce cellular Ca load, further compromising systolic contraction during HF.

Methods And Results: Anesthetized tachypaced HF swine received ranolazine (n = 9) or mexiletine (n = 7) as boluses, then as infusions; the same experiments were performed in 10 nonpaced controls.

Role of suppression of the inward rectifier current in terminal action potential repolarization in the failing heart.

Background: The failing heart exhibits an increased arrhythmia susceptibility that is often attributed to action potential (AP) prolongation due to significant ion channel remodeling. The inwardly rectifying K current (I) has been reported to be reduced, but its contribution to shaping the AP waveform and cell excitability in the failing heart remains unclear.

Objective: The purpose of this study was to define the effect of I suppression on the cardiac AP and excitability in the normal and failing hearts.

Risk factors and the effect of cardiac resynchronization therapy on cardiac and non-cardiac mortality in MADIT-CRT.

Aims: To understand modes of death and factors associated with the risk for cardiac and non-cardiac deaths in patients with cardiac resynchronization therapy with implantable cardioverter-defibrillator (CRT-D) vs. implantable cardioverter-defibrillator (ICD) therapy, which may help clarify the action and limitations of cardiac resynchronization therapy (CRT) in relieving myocardial dysfunction.

Methods And Results: In Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT), during 4 years of follow-up, 169 (9.

Improving clinical practice guidelines for practicing cardiologists.

Cardiac-related clinical practice guidelines have become an integral part of the practice of cardiology. Unfortunately, these guidelines are often long, complex, and difficult for practicing cardiologists to use. Guidelines should be condensed and their format upgraded, so that the key messages are easier to comprehend and can be applied more readily by those involved in patient care.

A senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism.

Senescence, perceived as a cancer barrier, is paradoxically associated with inflammation, which promotes tumorigenesis. Here, we characterize a distinct low-grade inflammatory process in stressed epithelium that is related to para-inflammation; this process either represses or promotes tumorigenesis, depending on p53 activity. Csnk1a1 (CKIα) downregulation induces a senescence-associated inflammatory response (SIR) with growth arrest in colorectal tumors, which loses its growth control capacity in the absence of p53 and instead, accelerates growth and invasiveness.

Differing effects of cardiac resynchronization therapy on long-term mortality in patient subgroups of MADIT-CRT defined by baseline conduction and 1-year post-treatment left ventricular remodeling.

Background: Long-term mortality data after cardiac resynchronization therapy with implanted defibrillator (CRT-D) in minimally symptomatic patients are limited.

Objective: To clarify influences on long-term mortality after CRT-D, we assessed MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy) patient outcomes by baseline conduction abnormality and 1-year posttreatment remodeling.

Methods: MADIT-CRT followed 1820 patients assigned to CRT-D or implanted cardioverter-defibrillator (ICD) only.

CKIα ablation highlights a critical role for p53 in invasiveness control.

The mature gut renews continuously and rapidly throughout adult life, often in a damage-inflicting micro-environment. The major driving force for self-renewal of the intestinal epithelium is the Wnt-mediated signalling pathway, and Wnt signalling is frequently hyperactivated in colorectal cancer. Here we show that casein kinase Iα (CKIα), a component of the β-catenin-destruction complex, is a critical regulator of the Wnt signalling pathway.

Response to preventive cardiac resynchronization therapy in patients with ischaemic and nonischaemic cardiomyopathy in MADIT-CRT.

Aims: There are no data regarding the differential response to cardiac resynchronization therapy with defibrillator (CRT-D) by the aetiology of cardiomyopathy in mildly symptomatic patients. We evaluated the outcome of patients enrolled in MADIT-CRT by ischaemic and non-ischaemic aetiology of cardiomyopathy (ICM and non-ICM, respectively).

Methods And Results: The clinical response to CRT-D was assessed among ICM (n = 1046) and non-ICM (n = 774) patients enrolled in MADIT-CRT during an average follow-up of 2.

Bone modifiers and the quest to slow progression of aortic stenosis.

Aortic stenosis (AS) will likely become increasingly frequent with the aging of the American population. The difficulties in treating elderly patients with critical AS emphasize the potential value of a strategy to slow the advancement of aortic valve calcification. Recent prospective trials of statins and angiotensin-converting enzyme inhibitors have been disappointing.

Gender differences and risk of ventricular tachycardia or ventricular fibrillation.

Background: Healthy women have longer QT intervals and more drug-induced proarrhythmia compared to men, yet those given implantable cardioverter-difibrillators (ICDs) for ischemic cardiomyopathy have fewer episodes of ventricular tachycardia/ventricular fibrillation (VT/VF) than men. The role of repolarization duration and stability in arrhythmogenesis in men and women with structural heart disease has not been explored.

Objectives: The purpose of this study was to analyze repolarization differences between men and women and their relation to the risk of VT/VF.

An eh1-like motif in odd-skipped mediates recruitment of Groucho and repression in vivo.

Drosophila Groucho, like its vertebrate Transducin-like Enhancer-of-split homologues, is a corepressor that silences gene expression in numerous developmental settings. Groucho itself does not bind DNA but is recruited to target promoters by associating with a large number of DNA-binding negative transcriptional regulators. These repressors tether Groucho via short conserved polypeptide sequences, of which two have been defined.

Atherosclerotic risk genotypes and recurrent coronary events after myocardial infarction.

The association of a group of prespecified atherosclerotic risk genotypes with recurrent coronary events (coronary-related death, nonfatal myocardial infarction, or unstable angina) was investigated in a cohort of 1,008 patients after infarction during an average follow-up of 28 months. We used a carrier-ship approach with time-dependent survivorship analysis to evaluate the average risk of each carried genotype. Contrary to expectation, the hazard ratio for recurrent coronary events per carried versus noncarried genotype was 0.

QT interval variability and spontaneous ventricular tachycardia or fibrillation in the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II patients.

Objectives: This study aimed to determine whether increased QT interval variability is associated with an increased risk for ventricular tachycardia (VT) or ventricular fibrillation (VF), documented by interrogation of the implantable cardioverter-defibrillator (ICD), in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II.

Background: Unstable repolarization has been proposed as a risk factor for re-entrant arrhythmias, but confirmatory data from clinical trials are lacking.

Methods: The QT variability was assessed in 10-min, resting high-resolution electrocardiogram recordings at study entry using a semiautomated algorithm that measured beat-to-beat QT duration in 817 MADIT II patients.