Extent and magnitude of low-voltage areas assessed by ultra-high-density electroanatomical mapping correlate with left atrial function.

INTRODUCTION: The extent of left atrial (LA) adverse remodeling as a cardiac disease marker has become increasingly important. In patients with atrial fibrillation (AF), atrial remodeling (AR) is accompanied by increased mortality. The relation between LA function and the extent of low-voltage areas (LVAs) has not yet been systematically investigated. METHODS: In patients with AF undergoing catheter-ablation, LA was studied using echocardiography and ultra-high-density mapping (Rhythmia®). Fibrosis (i.e. extent of LVAs) was estimated by quantifying areas with bipolar electrogram amplitudes of ≤0.5, ≤0.4, ≤0.3, ≤0.2 or ≤0.1 mV. RESULTS: A total of 22 patients with a mean LVEF of 53 ±â€¯2% was studied. Mean LA volume index (LAVI) was significantly increased at 39 ±â€¯3 ml/m2 indicating AR. Size of LVAs was 57 ±â€¯7 cm2 representing 47 ±â€¯5% of the total LA area (low-voltage set to ≤0.5 mV). With low-voltage set to ≤0.4, ≤0.3, ≤0.2 and ≤0.1, total area decreased to 34 ±â€¯6, 28 ±â€¯6, 22 ±â€¯5 and 12 ±â€¯3 cm2. LAVI positively correlated with the extent of LVAs at all cut-offs. Mean LA emptying fraction was 42 ±â€¯3% and showed a negative correlation with LVAs with low-voltage set to ≤0.4 mV. Moreover, mean LA strain was 13 ±â€¯2% and correlated with LVAs with low-voltage at all cut-offs further supporting the notion that the extent of LVAs impacts LA function. Notably, with low-voltage set to ≤0.2, ≤0.3 and ≤0.4 mV impaired LA strain was detected with an accuracy of >76% (p < 0.05). CONCLUSION: Structural (i.e. LAVI) and functional (i.e. LA emptying fraction and LA strain) parameters of the LA correlate with the extent of LVAs.

Pathophysiological and therapeutic implications in patients with atrial fibrillation and heart failure.

Heart failure and atrial fibrillation are common and responsible for significant mortality of patients. Both share the same risk factors like hypertension, ischemic heart disease, diabetes, obesity, arteriosclerosis, and age. A variety of microscopic and macroscopic changes favor the genesis of atrial fibrillation in patients with preexisting heart failure, altered subcellular Ca2+ homeostasis leading to increased cellular automaticity as well as concomitant fibrosis that are induced by pressure/volume overload and altered neurohumoral states. Atrial fibrillation itself promotes clinical deterioration of patients with preexisting heart failure as atrial contraction significantly contributes to ventricular filling. In addition, atrial fibrillation induced tachycardia can even further compromise ventricular function by inducing tachycardiomyopathy. Even though evidence has been provided that atrial functions significantly and independently of confounding ventricular pathologies, correlate with mortality of heart failure patients, rate and rhythm controls have been shown to be of equal effectiveness in improving mortality. Yet, it also has been shown that cohorts of patients with heart failure benefit from a rhythm control concept regarding symptom control and hospitalization. To date, amiodarone is the most feasible approach to restore sinus rhythm, yet its use is limited by its extensive side-effect profile. In addition, other therapies like catheter-based pulmonary vein isolation are of increasing importance. A wide range of heart failure-specific therapies are available with mixed impact on new onset or perpetuation of atrial fibrillation. This review highlights pathophysiological concepts and possible therapeutic approaches to treat patients with heart failure at risk for or with atrial fibrillation.

Dyssynchronous calcium removal in heart failure-induced atrial remodeling.

We tested the hypothesis that in atrial myocytes from a rabbit left ventricular heart failure (HF) model, spatial inhomogeneity and temporal dyssynchrony of Ca removal during excitation-contraction coupling together with increased Na/Ca exchange (NCX) activity generate a substrate for proarrhythmic Ca release. Ca removal occurs via Ca reuptake into the sarcoplasmic reticulum and extrusion via NCX exclusively in the cell periphery since rabbit atrial myocytes lack transverse tubules. Ca removal kinetics were assessed by the time constant τ of decay of local peripheral subsarcolemmal (SS) and central (CT) action potential (AP)-induced Ca transients (CaTs) recorded in confocal line scan mode (using Fluo-4). Spatial and temporal dyssynchrony of Ca removal was quantified by CV TAU, defined as the standard deviation of local τ along the transverse cell axis divided by mean τ. In normal cells CT CaT decline was slower compared with the SS domain, while in HF cells decline was accelerated, became equal in SS and CT regions, and a significant increase of CV TAU indicated an increased Ca removal dyssynchrony. In HF atrial cells NCX upregulation was accompanied by an overall higher incidence of spontaneous Ca waves and a higher propensity of arrhythmogenic Ca waves, defined as waves that triggered APs due to NCX-mediated membrane depolarization. NCX inhibition normalized CV TAU in HF atrial cells and decreased the propensity of Ca waves. In summary, HF atrial myocytes show accelerated but dyssynchronous diastolic Ca removal and altered sarcoplasmic reticulum Ca-ATPase (SERCA) and NCX activity that result in increased susceptibility to arrhythmia.

Socio-economic effects and cost saving potential of remote patient monitoring (SAVE-HM trial).

OBJECTIVE: In the SAVE-trial we evaluated the safety, reliability and improvements of patient management using the BIOTRONIK Home Monitoring®-System (HM) in pacemaker (PM) and implanted cardioverter defibrillator (ICD) patients. DESIGN: 115 PM (Module A) and 36 ICD-patients (Module B) were recruited 3 months after implantation. PATIENTS: 65 patients in Module A were randomised to HM-OFF and had one scheduled outpatient clinic follow-up(FU) per year, whereas patients randomised to HM-ON were equipped with the mobile transmitter and discharged without any further scheduled in-office FU. In Module B 18 patients were randomised to HM-OFF and followed by standard outpatient clinic controls every 6 months; 18 patients were randomised to HM-ON receiving remote monitoring plus one outpatient clinic visit per year; unscheduled follow-ups were performed when necessary. RESULTS: The average follow-up period was 17.1 ± 9.2 months in Module A and 26.3 ± 8.6 months in Module B. In both modules, the number of FUs per year was significantly reduced (Module A HM-ON 0.29 ± 0.6 FUs/year vs HM-OFF 0.53 ± 0.5 FUs/year; p b 0.001; Module B HM-ON 0.87 ± 0.25 vs HM-OFF 1.73 ± 0.53 FU/year,p b 0.001). Cost analysis was significantly lower in the HM-ON group compared to the HM-OFF group (18.0 ± 41.3 and 22.4 ± 26.9 € respectively; p b 0.003). 93% of the unscheduled visits in Module B were clinically indicated,whereas 55% of the routine FUs were classified as clinically unnecessary. CONCLUSION: Remote home monitoring of pacemaker and ICD devices was safe, reduced overall hospital visits, and detected events that mandated unscheduled visits.

JTV519 (K201) reduces sarcoplasmic reticulum Ca²âº leak and improves diastolic function in vitro in murine and human non-failing myocardium.

BACKGROUND AND PURPOSE: Ca²âº leak from the sarcoplasmic reticulum (SR) via ryanodine receptors (RyR2s) contributes to cardiomyocyte dysfunction. RyR2 Ca²âº leak has been related to RyR2 phosphorylation. In these conditions, JTV519 (K201), a 1,4-benzothiazepine derivative and multi-channel blocker, stabilizes RyR2s and decrease SR Ca²âº leak. We investigated whether JTV519 stabilizes RyR2s without increasing RyR2 phosphorylation in mice and in non-failing human myocardium and explored underlying mechanisms. EXPERIMENTAL APPROACH: SR Ca²âº leak was induced by ouabain in murine cardiomyocytes. [Ca²âº]-transients, SR Ca²âº load and RyR2-mediated Ca²âº leak (sparks/waves) were quantified, with or without JTV519 (1 µmol·L⁻¹). Contribution of Ca²âº -/calmodulin-dependent kinase II (CaMKII) was assessed by KN-93 and Western blot (RyR2-Ser(2814) phosphorylation). Effects of JTV519 on contractile force were investigated in non-failing human ventricular trabeculae. KEY RESULTS: Ouabain increased systolic and diastolic cytosolic [Ca²âº](i) , SR [Ca²âº], and SR Ca²âº leak (Ca²âº spark (SparkF) and Ca²âº wave frequency), independently of CaMKII and RyR-Ser(2814) phosphorylation. JTV519 decreased SparkF but also SR Ca²âº load. At matched SR [Ca²âº], Ca²âº leak was significantly reduced by JTV519, but it had no effect on fractional Ca²âº release or Ca²âº wave propagation velocity. In human muscle, JTV519 was negatively inotropic at baseline but significantly enhanced ouabain-induced force and reduced its deleterious effects on diastolic function. CONCLUSIONS AND IMPLICATIONS: JTV519 was effective in reducing SR Ca²âº leak by specifically regulating RyR2 opening at diastolic [Ca²âº](i) in the absence of increased RyR2 phosphorylation at Ser(2814) , extending the potential use of JTV519 to conditions of acute cellular Ca²âº overload.

Role of connexin 43 in ischemic preconditioning does not involve intercellular communication through gap junctions.

Connexin 43 (Cx 43) has recently been implicated in protection of ischemic preconditioning. Cx 43 colocalization with protein kinase C and p38 mitogen-activated protein kinase is increased in preconditioned myocardium, Cx 43 phosphorylation is preserved in preconditioned myocardium, and hearts from Cx 43-deficient mice cannot be preconditioned. It is, however, unclear whether the important role of Cx 43 relates to intercellular communication through gap junctions or its function in volume homeostasis. To address this issue, we used isolated cardiomyocytes, which no longer-form gap junctions, from wild-type (n = 5) and heterozygous Cx 43-deficient mice (n = 8) and subjected them to 2 h simulated ischemia (hypoxia, acidosis) and an additional challenge by extracellular hypo-osmolarity (from 310 to 250 mOsm/l). Viability (trypan blue exclusion) was well maintained in normoxic wild-type cardiomyocytes (54 +/- 5% at baseline vs. 46 +/- 4 (mean +/- S.D.) % at 2 h). With simulated ischemia, viability was reduced to 17 +/- 5%. Preconditioning by a preceding exposure to 10 min simulated ischemia and 15 min reoxygenation preserved viability after 2 h simulated ischemia (36 +/- 1%, P < 0.001 vs. simulated ischemia). In Cx 43-deficient cardiomyocytes, viability was also well maintained in normoxia (56 +/- 10% vs. 44 +/- 10%). Viability was also reduced to 17 +/- 6% with 2 h simulated ischemia. In contrast to wild-type cells, preconditioning did not prevent the reduction in viability (18 +/- 8%). In conclusion, Cx 43 is essential for preconditioning in the absence of gap junctions, supporting its function through improved volume regulation.

Extrapolation to zero-flow pressure in cerebral arteries to estimate intracranial pressure.

BACKGROUND: Cerebral perfusion pressure (CPP) is commonly calculated from the difference between arterial blood pressure (AP) and intracranial pressure (ICP). ICP can be considered the effective downstream pressure of the cerebral circulation. Consequently, cerebral circulatory arrest would occur when AP equals ICP. Estimation of AP for zero-flow pressure (ZFP) may thus allow estimation of ICP. We estimated ZFP from cerebral pressure-flow velocity relationships so that ICP could be measured by transcranial Doppler sonography. METHODS: We studied 20 mechanically ventilated patients with severe head injury, in whom ICP was monitored by epidural pressure transducers. AP was measured with a radial artery cannula. Blood flow velocity in the middle cerebral artery (V(MCA)) ipsilateral to the site of ICP measurement was measured with a 2 MHz transcranial Doppler probe. All data were recorded by a microcomputer from analogue-digital converters. ZFP was extrapolated by regression analysis of AP-V(MCA) plots and compared with simultaneous measurements of ICP. RESULTS: ZFP estimated from AP-V(MCA) plots was linearly related to ICP over a wide range of values (r=0.93). There was no systematic difference between ZFP and ICP. Limit of agreement (2 SD) was 15.2 mm Hg. Short-term variations in ICP were closely followed by changes in ZFP. CONCLUSION: Extrapolation of cerebral ZFP from instantaneous AP-V(MCA) relationships enables detection of severely elevated ICP and may be a useful and less invasive method for CPP monitoring than other methods.