New therapeutic target for the non-electrophysiological signaling in atrial fibrosis and fibrillation such as inflammation

AbstractWe have experimentally established appropriate models of atrial fibrillation (AF) with atrial interstitial fibrosis. Two approaches were adopted. Firstly, left atrial fibrosis was induced by continuous infusion of angiotensin II (AII). In an electrophysiological study using isolated perfused heart, AF was easily induced following AII treatment. Repeated whole-body hyperthermia led to the induction of heat-shock protein 72, which resulted in attenuation of AII-induced left atrial fibrosis and suppression of AF inducibility. Secondly, atrial fibrosis was induced by pressure overload by abdominal aortic constriction (AAC). AAC enhanced left atrial expression of monocyte chemoattractant protein-1 and activity of matrix metalloproteinase-9. Treatment with pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, resulted in attenuation of pressure overload-induced left atrial fibrosis and suppression of AF inducibility. In the same AAC model, the effects of candesartan on gap junction remodeling were investigated. Connexin 43 (Cx43) of the left atria was firmly located in the intercalated disks in control rats. A progressive redistribution of Cx43 from the intercalated disk to the lateral surface (lateralization) was observed in AAC rats. Candesartan prevented left Cx43 lateralization. Thus, heat-shock proteins, pioglitazone, and candesartan could be novel therapeutic approaches to prevent atrial fibrosis and AF

Noninvasive assessment of the cardiac baroreflex Response to downward tilting and comparison with the phenylephrine method

AbstractOBJECTIVESWe studied the relation between changes in systolic blood pressure and RR interval during downward tilting in comparison with assessment of baroreflex sensitivity (BRS) measured by the phenylephrine method (Phe-BRS) and with measures of heart rate variability (HRV).BACKGROUNDThe method most extensively used for assessing BRS involves bolus injections of phenylephrine. Several noninvasive methods proposed to assess BRS have not been widely applied in the clinical setting.METHODSSixteen healthy male volunteers were studied (mean age ± SD 27.5 ± 4.6 years). Arterial blood pressure using tonometry and electrocardiogram was simultaneously recorded. After 20 min of 70° upright tilting, the table was returned to supine position at a speed of 3.2°/s. Subsequently, BRS was assessed using an intravenous bolus injection of phenylephrine (2 to 3 μg/kg). Heart rate variability under resting conditions also was analyzed.RESULTSIn all subjects, a beat to beat systolic blood pressure increase associated with corresponding RR interval lengthening was observed during downward tilting as well as during phenylephrine administration. During both testing procedures, these two variables showed linear correlation, and the slope of regression line during downward tilting (DT-BRS) correlated significantly with Phe-BRS (r = 0.79, p = 0.0003). The DT- and Phe-BRS also correlated significantly with the high frequency component of resting HRV (r = 0.70, p = 0.0023 for DT-BRS; r = 0.58, p = 0.0185 for Phe-BRS).CONCLUSIONSWe conclude that in a small homogeneous group DT-BRS provided an assessment of reflex cardiac vagal function comparable to that obtained by the phenylephrine method

QT Interval Revisited —Not Just the Matter of “Interval,” but “Dynamics, Variability and Morphology” Matter!—

Recently, the effects of QT interval prolongation have received more attention among clinicians, industry, and official regulatory agencies. Some have advocated the total elimination or discontinuing development of drugs which prolong the QT interval. In this review, we will give a brief overview of the pathophysiology and the dynamic variability and morphology of the QT interval. From the view point of arrhythmogenesis, QT interval prolongation with increased heterogeneity of ventricular repolarization is critical. The problem is how to detect such an abnormal repolarization. To detect heterogeneity, a new index should be developed and validated, and it must incorporate QT variability and morphology of the T wave. The heart rate correction of the QT interval is also an important issue, and disclosing conflict-corrected QT intervals depend on the formulae used. Not just QT interval prolongation is important; what also matters is the heterogeneity of ventricular repolarization

Higher Cholesterol Absorption Marker at Baseline Predicts Fewer Cardiovascular Events in Elderly Patients Receiving Hypercholesterolemia Treatment: The KEEP Study

Background Higher cholesterol absorption has been reported to be related to a higher incidence of cardiovascular events (CVEs). The KEEP (Kyushu Elderly Ezetimibe Phytosterol) study, a substudy of the EWTOPIA 75 (Ezetimibe Lipid‐Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older) study, investigated the relationships of cholesterol absorption and synthesis markers with CVEs in older old individuals with hypercholesterolemia, particularly in relation to ezetimibe treatment. Methods and Results Eligible patients were those aged ≥75 years who had low‐density lipoprotein cholesterol ≥140 mg/dL, no history of coronary artery disease, and no recent use of lipid‐lowering drugs. Participants were randomly assigned into a diet‐only or diet‐plus‐ezetimibe group. Baseline and 24‐week follow‐up blood samples were analyzed for cholesterol absorption (eg, campesterol) and synthesis markers (eg, lathosterol). Of 1287 patients, 1061 patients with baseline measurement were analyzed. Over a median follow‐up of 4.0 years, 64 CVEs occurred. Higher campesterol levels at baseline were significantly associated with a lower risk of CVEs. After adjustment for sex, age, and treatment, the hazard ratios for the lowest to highest quartile categories of baseline campesterol were 1.00 (reference), 0.59 (95% CI, 0.30–1.17), 0.44 (95% CI, 0.21–0.94), and 0.44 (95% CI, 0.21–0.93), respectively (trend P=0.01). This association persisted after further adjustment for hypertension, diabetes, and other cardiovascular risk factors. Neither interactions with ezetimibe treatment nor mediating effects of the changes in cholesterol absorption markers were observed. Conclusions The KEEP study indicated that higher campesterol levels without lipid‐lowering drugs were associated with a lower incidence of CVEs in older old individuals with hypercholesterolemia who were subsequently treated with diet or ezetimibe. Registration URL: https://www.umin.ac.jp; unique identifier: UMIN000017769