Juan Cinca

Atrial Fibrillation Is Associated With Increased Spontaneous Calcium Release From the Sarcoplasmic Reticulum in Human Atrial Myocytes

Background—Spontaneous Ca2+ release from the sarcoplasmic reticulum (SR) can generate afterdepolarizations, and these have the potential to initiate arrhythmias. Therefore, an association may exist between spontaneous SR Ca2+ release and initiation of atrial fibrillation (AF), but this has not yet been reported. Methods and Results—Spontaneous Ca2+ release from the SR, manifested as Ca2+ sparks and Ca2+ waves, was recorded with confocal microscopy in atrial myocytes isolated from patients with and those without AF. In addition, the spontaneous inward current associated with Ca2+ waves was measured with the use of the perforated patch-clamp technique. The Ca2+ spark frequency was higher in 8 patients with AF than in 16 patients without (6.0±1.2 versus 2.8±0.8 sparks/mm per second, P<0.05). Similarly, the spontaneous Ca2+ wave frequency was greater in patients with AF (2.8±0.5 versus 1.1±0.3 waves/mm per second, P<0.01). The spontaneous inward current frequency was also higher in 10 patients with AF than in 13 patients without this arrhythmia (0.101±0.028 versus 0.031±0.007 per second, P<0.05, at a clamped potential of −80 mV). In contrast, both the Ca2+ released from the SR and the Na+-Ca2+ exchange rate induced by a rapid caffeine application were comparable in patients with and without AF. Conclusions—The observed increase in spontaneous Ca2+ release in patients with AF probably is due to an upregulation of the SR Ca2+ release channel activity, which may contribute to the development of AF.

The MUSIC Risk score: a simple method for predicting mortality in ambulatory patients with chronic heart failure.

AIMS The prognosis of chronic heart failure (CHF) is extremely variable, although generally poor. The purpose of this study was to develop prognostic models for CHF patients. METHODS AND RESULTS A cohort of 992 consecutive ambulatory CHF patients was prospectively followed for a median of 44 months. Multivariable Cox models were developed to predict all-cause mortality (n = 267), cardiac mortality (primary end-point, n = 213), pump-failure death (n = 123), and sudden death (n = 90). The four final models included several combinations of the same 10 independent predictors: prior atherosclerotic vascular event, left atrial size >26 mm/m(2), ejection fraction < or =35%, atrial fibrillation, left bundle-branch block or intraventricular conduction delay, non-sustained ventricular tachycardia and frequent ventricular premature beats, estimated glomerular filtration rate <60 mL/min/1.73 m(2), hyponatremia < or =138 mEq/L, NT-proBNP >1.000 ng/L, and troponin-positive. On the basis of Cox models, the MUSIC Risk scores were calculated. A cardiac mortality score >20 points identified a high-risk subgroup with a four-fold cardiac mortality risk. CONCLUSION A simple score with a limited number of non-invasive variables successfully predicted cardiac mortality in a real-life cohort of CHF patients. The use of this model in clinical practice identifies a subgroup of high-risk patients that should be closely managed.

PITX2 Insufficiency Leads to Atrial Electrical and Structural Remodeling Linked to Arrhythmogenesis

Background— Pitx2 is a homeobox transcription factor that plays a pivotal role in early left/right determination during embryonic development. Pitx2 loss-of-function mouse mutants display early embryonic lethality with severe cardiac malformations, demonstrating the importance of Pitx2 during cardiogenesis. Recently, independent genome-wide association studies have provided new evidence for a putative role of PITX2 in the adult heart. These studies have independently reported several risk variants close to the PITX2 locus on chromosome 4q25 that are strongly associated with atrial fibrillation in humans. Methods and Results— We show for the first time that PITX2C expression is significantly decreased in human patients with sustained atrial fibrillation, thus providing a molecular link between PITX2 loss of function and atrial fibrillation. In addition, morphological, molecular, and electrophysiological characterization of chamber-specific Pitx2 conditional mouse mutants reveals that atrial but not ventricular chamber-specific deletion of Pitx2 results in differences in the action potential amplitude and resting membrane potential in the adult heart as well as ECG characteristics of atrioventricular block. Lack of Pitx2 in atrial myocardium impairs sodium channel and potassium channel expression, mediated in part by miRNA misexpression. Conclusions— This study thus identifies Pitx2 as an upstream transcriptional regulator of atrial electric function, the insufficiency of which results in cellular and molecular changes leading to atrial electric and structural remodeling linked to arrhythmogenesis.

Soluble ST2 for Predicting Sudden Cardiac Death in Patients With Chronic Heart Failure and Left Ventricular Systolic Dysfunction

OBJECTIVES We studied whether the measurement of the soluble form of ST2 (sST2), an interleukin-1 receptor family member, could identify heart failure (HF) patients at risk of sudden cardiac death (SCD). BACKGROUND The prediction of SCD remains an important challenge in patients with mild-to-moderate chronic HF. Concentrations of sST2 have been found increased and related to worse long-term outcomes in patients with acute HF. Whether sST2 has a prognostic role in SCD is unknown. METHODS A nested case-control study was performed on 36 cases of SCD and 63 control patients (matched for age, sex, and left ventricular ejection fraction) obtained from the MUSIC (MUerte Súbita en Insuficiencia Cardíaca) registry, a 3-year multicenter registry of ambulatory HF patients (New York Heart Association functional class II to III, left ventricular ejection fraction < or =45%). Demographic, clinical, echocardiographic, electrical, and biochemical data were collected at enrollment. RESULTS Concentrations of sST2 were greater among decedents (0.23 ng/ml [interquartile range 0.16 to 0.43 ng/ml] vs. 0.12 ng/ml [interquartile range 0.06 to 0.23 ng/ml], p = 0.001) and were predictive of experiencing SCD (+0.1 ng/ml, odds ratio: 1.39, 95% confidence interval: 1.09 to 1.78, p = 0.006). On the basis of a combined biomarker status, only 4% of patients experienced SCD for neither sST2 nor N-terminal pro-B-type natriuretic peptide (NT-proBNP) above receiver-operator characteristic-derived cut-off points (0.15 ng/ml and 2,000 ng/l, respectively), 34% for either biomarker above, and 71% for both biomarkers above (p < 0.001 for trend). This combined variable added incremental prognostic value to the multivariable regression model (p < 0.001). CONCLUSIONS Elevated sST2 concentrations are predictive of SCD in patients with chronic HF and provide complementary information to NT-proBNP levels. A combined biomarker approach may have an impact on clinical decision-making.

Right ventricular infarction: Relationships between ST segment elevation in V4R and hemodynamic, scintigraphic, and echocardiographic findings in patients with acute inferior myocardial infarction

The relationship between ST segment elevation on the right precordial lead V4R and the hemodynamic, echocardiographic, and myocardial scintigrapic signs suggestive of right ventricular (RV) infarction was studied in 42 patients with acute inferior myocardial infarction. Twenty-two patients had ST segment elevation in V4R. Among these patients, a significant correlation was demonstrated between V4R ST segment elevation and the hemodynamic (p less than 0.001), scintigraphic (p less than 0.001), and echographic (p less than 0.02) criteria for acute RV infarction. These results support the validity of this new electrocardiographic sign as a practical means in aiding the clinical detection of RV involvement with acute transmural inferior myocardial infarction.

Changes in Myocardial Electrical Impedance Induced by Coronary Artery Occlusion in Pigs With and Without Preconditioning Correlation With Local ST-Segment Potential and Ventricular Arrhythmias

BACKGROUND Myocardial ischemia increases tissue electrical resistivity leading to cell-to-cell uncoupling, and this effect is delayed by ischemic preconditioning in isolated myocardium. Alterations in myocardial resistivity elicited by ischemia in vivo may influence arrhythmogenesis and local ST-segment changes, but this is not well known. METHODS AND RESULTS Myocardial impedance (resistivity [omega x cm] and phase angle [degrees]), epicardial ST segment, and ventricular arrhythmias were analyzed during 4 hours of coronary artery occlusion in 11 anesthetized open-chest pigs; these were compared with 13 other pigs submitted to a similar coronary occlusion preceded by ischemic preconditioning. Myocardial resistivity rose slowly during the first 34+/-7 minutes of occlusion (237+/-41 to 359+/-59 omega x cm), increased rapidly to 488+/-100 omega x cm at 60 minutes, and reached a plateau value (718+/-266 omega x cm, ANOVA; P<.01) at 150+/-69 minutes. By contrast, phase-angle changes began after 17 minutes of ischemia (-3.0+/-1.6 degrees to -4.2+/-1.2 degrees at 29+/-8 minutes) and evolved faster thereafter (-12.5+/-5.3 degrees at 144+/-56 minutes). Marked changes in myocardial impedance were observed during the reversion of ST-segment elevation that occurred 1 to 4 hours after occlusion, but impedance changes were less apparent during the early ST-segment recovery seen at 15 to 35 minutes of ischemia. The second arrhythmia peak (30+/-5 minutes) coincided with the fast change in tissue impedance, and both were delayed (P<.05) by ischemic preconditioning. CONCLUSIONS A rapid impairment of myocardial impedance occurs after 30 minutes of coronary occlusion, and its onset is better defined by shift in phase angle than by rise in tissue resistivity. Phase 1b arrhythmias are associated with marked impedance changes, and both are delayed by preconditioning. Reversion of ST-segment elevation is partially associated with impairment of myocardial impedance, but other factors play a role as well.

Effect of aging on the pluripotential capacity of human CD105+ mesenchymal stem cells

Whether aging modifies mesenchymal stem cell (MSC) properties is unknown.

Heart rate turbulence predicts all-cause mortality and sudden death in congestive heart failure patients

BACKGROUND Abnormal heart rate turbulence (HRT) has been documented as a strong predictor of total mortality and sudden death in postinfarction patients, but data in patients with congestive heart failure (CHF) are limited. OBJECTIVE The aim of this study was to evaluate the prognostic significance of HRT for predicting mortality in CHF patients in New York Heart Association (NYHA) class II-III. METHODS In 651 CHF patients with sinus rhythm enrolled into the MUSIC (Muerte Subita en Insuficiencia Cardiaca) study, the standard HRT parameters turbulence onset (TO) and slope (TS), as well as HRT categories, were assessed for predicting total mortality and sudden death. RESULTS HRT was analyzable in 607 patients, mean age 63 years (434 male), 50% of ischemic etiology. During a median follow up of 44 months, 129 patients died, 52 from sudden death. Abnormal TS and HRT category 2 (HRT2) were independently associated with increased all-cause mortality (HR: 2.10, CI: 1.41 to 3.12, P <.001 and HR: 2.52, CI: 1.56 to 4.05, P <.001; respectively), sudden death (HR: 2.25, CI: 1.13 to 4.46, P = .021 for HRT2), and death due to heart failure progression (HR: 4.11, CI: 1.84 to 9.19, P <.001 for HRT2) after adjustment for clinical covariates in multivariate analysis. The prognostic value of TS for predicting total mortality was similar in various groups dichotomized by age, gender, NYHA class, left ventricular ejection fraction, and CHF etiology. TS was found to be predictive for total mortality only in patients with QRS > 120 ms. CONCLUSION HRT is a potent risk predictor for both heart failure and arrhythmic death in patients with class II and III CHF.

A mutation in the sodium channel is responsible for the association of long QT syndrome and familial atrial fibrillation

BACKGROUND Type 3 long-QT syndrome (LQT-3) is caused by gain-of-function mutations in the SCN5A encoding the cardiac sodium channel. Familial atrial fibrillation (AF), previously considered a potassium channelopathy, has recently been related to sodium genetic variants, both in isolated forms and in patients with underlying heart disease. OBJECTIVE The purpose of this study was to describe the first family associating LQT-3 and AF due to a gain-of-function mutation in SCN5A and assess the usefulness of the sodium blocker flecainide in individuals with both phenotypes. METHODS Complete family screening was performed after identifying a proband showing paroxysmal AF and a long QT interval suggestive of LQT-3. Secondary causes of AF were ruled out in all individuals. Flecainide was used in two patients for LQT-3 diagnosis and therapeutic treatment of AF. Genetic screening was performed by direct sequencing of the exons and exon-intron boundaries of SCN5A. RESULTS We identified a three-generation family (eight members), all of them showing long QT intervals. Paroxysmal AF initiated between 20 and 35 years of age in all three adults. The flecainide test led to shortening of the QTc interval. Flecainide was also effective in acutely restoring sinus rhythm. A Y1795C mutation was identified in all members. CONCLUSION This is the first report showing an association of familial AF and LQT-3 due to a mutation in SCN5A. This finding provides further evidence of the role of SCN5A in AF. We also confirm the usefulness of flecainide in this particular complex phenotype, both as a diagnostic tool for LQT-3 and as an acute treatment for AF.

Lack of evidence of M-cells in porcine left ventricular myocardium

OBJECTIVE The aim of this study was to analyze whether cells with long action potential duration, fast Vmax, and spike-and-dome configuration (M-cells) are present in porcine left ventricular myocardium. METHODS Transmembrane action potentials (n = 505) of the left ventricle were recorded with conventional glass microelectrodes in an epicardial-endocardial direction at 2000 ms basic cycle length in 14 pigs. In 3 pigs, potentials were obtained at 1000, 2000, and 5000 ms cycle length before and after superfusion with quinidine HCl 1 microgram/ml. In addition, transmembrane potentials (n = 52) were recorded in 4 dogs at 2000 ms cycle length to verify the ability of our protocol to detect M-cells. RESULTS In pigs, action potential duration at 90% repolarization was shorter (ANOVA, P < 0.001) and Vmax slower (P < 0.001) in the epicardium than in the other transmural sites, but there were no regional differences in resting membrane potential or in action potential amplitude. Potentials with particularly long phase 3 or with spike-and-dome configuration were not observed. All myocardial sites displayed rate dependence of action potential duration (P = 0.02) which was transmurally homogeneous and persisted after quinidine exposure. The drug did not induce afterdepolarizations. In dogs, potentials with spike-and-dome configuration, long duration, and fast Vmax, like those described in M-cells, were detected in deep epicardial and midmyocardial areas. CONCLUSION The porcine left ventricular myocardium shows transmural differences in action potential duration and Vmax, but, unlike dogs, it lacks M-cells.