Fine tuning contractility: atrial sarcomere function in health and disease.

The molecular mechanisms of sarcomere proteins underlie the contractile function of the heart. Although our understanding of the sarcomere has grown tremendously, the focus has been on ventricular sarcomere isoforms due to the critical role of the ventricle in health and disease. However, atrial-specific or -enriched myofilament protein isoforms, as well as isoforms that become expressed in disease, provide insight into ways this complex molecular machine is fine-tuned. Here, we explore how atrial-enriched sarcomere protein composition modulates contractile function to fulfill the physiological requirements of atrial function. We review how atrial dysfunction negatively affects the ventricle and the many cardiovascular diseases that have atrial dysfunction as a comorbidity. We also cover the pathophysiology of mutations in atrial-enriched contractile proteins and how they can cause primary atrial myopathies. Finally, we explore what is known about contractile function in various forms of atrial fibrillation. The differences in atrial function in health and disease underscore the importance of better studying atrial contractility, especially as therapeutics currently in development to modulate cardiac contractility may have different effects on atrial sarcomere function.

Atrial Mechanics, Atrial Cardiomyopathy and Impact of Atrial Interventions.

Our comprehension of atrial mechanics, atrial cardiomyopathy and their clinical implications across various cardiovascular conditions has advanced significantly. Atrial interventions can have differing effects on atrial mechanics. With the rapid increase in the use of atrial interventions, it is crucial for investigators and clinicians to acknowledge the potential adverse effects of these interventions on atrial mechanics that might not be clinically significant at the time of interventions. Recognizing the preclinical stage of atrial maladaptation might enable early interventions before the development of irreversible atrial remodeling and clinical manifestation. We review normal atrial function and mechanics, and atrial cardiomyopathy in select cardiovascular conditions. We also summarize and discuss the current evidence of the impact of various atrial interventions on atrial function and mechanics.

Reference data for left ventricular filling and atrial function in children using cardiovascular magnetic resonance.

BACKGROUND: Diastolic dysfunction is associated with morbidity and mortality in multiple pediatric disease processes. Cardiovascular magnetic resonance (CMR) provides a non-invasive method of studying left ventricular (LV) diastolic dysfunction through the assessment of LV filling curves and left atrial (LA) volume and function. However, there are no normative data for LV filling curves and the standard method is time-intensive. This study aims to compare an alternate, more rapid method of obtaining LV filling curves to standard methodology and report normative CMR diastolic function data for LV filling curves and LA volumes and function. METHODS: Ninety-six healthy pediatric subjects (14.3 ± 3.4 years) with normal CMR defined by normal biventricular size and systolic function without late gadolinium enhancement were included. LV filling curves were generated by removing basal slices without myocardium present throughout the cardiac cycle and apical slices with poor endocardial delineation (compressed method), then re-generated including every phase of myocardium from apex to base (standard method). Indices of diastolic function included peak filling rate and time to peak filling. Systolic metrics included peak ejection rate and time to peak ejection. Both peak ejection and peak filling rates were indexed to end-diastolic volume. LA maximum, minimum and pre-contraction volumes were calculated using a biplane method. Inter-and intra-observer variability were assessed with intraclass correlation coefficient. Multivariable linear regression was used to assess the effects of body surface area (BSA), gender and age on metrics of diastolic function. RESULTS: BSA had the largest effect on LV filling curves. Normal LV filling data are reported for both compressed and standard methods. The time to perform the compressed method was significantly shorter than the standard method (median 6.1 min vs. 12.5 min, p < 0.001). Both methods had strong to moderate correlation for all metrics. Intra-observer reproducibility was moderate to high for all LV filling and LA metrics except for time to peak ejection and peak filling. CONCLUSIONS: We report reference values for LV filling metrics and LA volumes. The compressed method is more rapid and produces similar results to standard methodology, which may facilitate the use of LV filling in clinical CMR reporting.

Similarities and Differences between Three-Dimensional Speckle-Tracking Echocardiography-Derived Left and Right Atrial Volumes and Volume-Based Functional Properties in the Same Healthy Adults-A Detailed Analysis from the MAGYAR-Healthy Study.

Background and Objectives: It would be important to know what happens to the volume and volume-based functional properties of one atrium if the size of the other atrium is larger or smaller than the average. Therefore, the present study aimed to perform three-dimensional speckle-tracking echocardiography (3DSTE)-derived quantification of left atrial (LA) and right atrial (RA) volumes and volume-based functional properties to examine these associations in healthy adults with mean and lower or higher than mean atrial volumes. Materials and Methods: The present study consisted of 179 healthy volunteers with a mean age of 32.3 ± 12.3 years (92 males). Three-dimensional speckle-tracking echocardiography-derived LA and RA volumes and volume-based functional properties were determined in all cases. Results: When different LA or RA volume groups were evaluated, both LA and RA showed the same pattern of volume changes in all phases of atrial function with higher LA or RA volumes. In case of low and mean LA volumes, RA volumes were higher compared to their LA counterpart. In case of mean and high RA volumes, RA volumes proved to be higher as well. In case of mean LA or RA volumes, differences between LA and RA stroke volumes (SVs) could not be detected, but all atrial emptying fractions (EFs) were lower for RA than for LA. Some differences were detected in counterpart LA/RA total, passive, and active atrial SVs and EFs values in the presence of lower/higher than mean LA/RA volume. Conclusions: In case of mean LA or RA volumes, RA volumes are higher compared to their LA counterpart, LA-SVs and RA-SVs are similar, but atrial EFs are lower for RA than for LA. If lower/higher than mean LA or RA volumes are present, some differences in patterns of changes in counterpart atrial volumes-SVs and EFs-could be detected.

Atrial function in paroxysmal AF patients with and without heart failure with preserved ejection fraction: Data from the AF-RISK study.

Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) are 2 cardiovascular conditions that often coexist. Strain phases of both the left and right atria are more impaired in paroxysmal AF patients with HFpEF than those without HFpEF in spite of comparable global longitudinal strain of the left ventricle. Atrial function may differentiate paroxysmal AF patients with HFpEF from those without HFpEF.

Alpha and beta myosin isoforms and human atrial and ventricular contraction.

Human atrial and ventricular contractions have distinct mechanical characteristics including speed of contraction, volume of blood delivered and the range of pressure generated. Notably, the ventricle expresses predominantly ß-cardiac myosin while the atrium expresses mostly the α-isoform. In recent years exploration of the properties of pure α- & ß-myosin isoforms have been possible in solution, in isolated myocytes and myofibrils. This allows us to consider the extent to which the atrial vs ventricular mechanical characteristics are defined by the myosin isoform expressed, and how the isoform properties are matched to their physiological roles. To do this we Outline the essential feature of atrial and ventricular contraction; Explore the molecular structural and functional characteristics of the two myosin isoforms; Describe the contractile behaviour of myocytes and myofibrils expressing a single myosin isoform; Finally we outline the outstanding problems in defining the differences between the atria and ventricles. This allowed us consider what features of contraction can and cannot be ascribed to the myosin isoforms present in the atria and ventricles.

Sex as a main determinant of bi-atrial acute and chronic adaptation to exercise.

PURPOSE: Athlete's heart encompasses multiple physiological cardiac adaptations, although less is known at atrial level. How sex may influence the type and extent of atrial adaptations to exercise stimuli is also unknown. Our objective was to compare gender differences of echocardiographic atrial function indices in response to exercise in endurance athletes (EAs). METHODS: Highly trained (> 10 h/week) endurance athletes performed a maximal cardiopulmonary exercise test (CPET). Echocardiographic evaluation was performed at rest and immediately after exercise. Atria analysis consisted of standard and speckle-tracking echocardiographic assessment of atrial dimensions and contractile, reservoir, and conduit functions with myocardial deformation. RESULTS: 80 EAs (55% women) were enrolled and performed excellent CPET (129.6% of predicted VO2 maximal consumption). At rest, left atrial (LA) volumes and strain were similar between men and women. Women had lower right atrial (RA) volumes (26.7 vs 32.9 ml/m2, p < 0.001) and higher reservoir and conduit strain absolute values. After exercise, women exhibited a larger improvement in reservoir and conduit LA strain, and the same trend was observed for the RA. In EAs with LA dilatation on baseline (~ 50%), women persistently showed higher increase in reservoir and conduit strain profile with exercise compared to men. CONCLUSION: In highly trained EAs, women have similar or even lower atrial dimensions remodelling compared to men, but better function based on reservoir and conduit strain values both at rest and in response to exercise. This phenomenon should be confirmed in larger studies and its potential role in the development of supraventricular arrhythmias, addressed in a specifically designed protocol.

Excitation-contraction coupling and calcium release in atrial muscle.

In cardiac muscle, the process of excitation-contraction coupling (ECC) describes the chain of events that links action potential induced myocyte membrane depolarization, surface membrane ion channel activation, triggering of Ca2+ induced Ca2+ release from the sarcoplasmic reticulum (SR) Ca2+ store to activation of the contractile machinery that is ultimately responsible for the pump function of the heart. Here we review similarities and differences of structural and functional attributes of ECC between atrial and ventricular tissue. We explore a novel "fire-diffuse-uptake-fire" paradigm of atrial ECC and Ca2+ release that assigns a novel role to the SR SERCA pump and involves a concerted "tandem" activation of the ryanodine receptor Ca2+ release channel by cytosolic and luminal Ca2+. We discuss the contribution of the inositol 1,4,5-trisphosphate (IP3) receptor Ca2+ release channel as an auxiliary pathway to Ca2+ signaling, and we review IP3 receptor-induced Ca2+ release involvement in beat-to-beat ECC, nuclear Ca2+ signaling, and arrhythmogenesis. Finally, we explore the topic of electromechanical and Ca2+ alternans and its ramifications for atrial arrhythmia.

Exercise physiology of the left atrium: quantity and timing of contribution to cardiac output.

Although the phases of left atrial (LA) function at rest have been studied, the physiological response of the LA to exercise is undefined. This study defines the exercise behavior of the normal left atrium by quantitating its volumetric response to graded effort. Healthy subjects (n = 131) were enrolled from the Health eHeart cohort. Echocardiograms were obtained at baseline and during ramped supine bicycle exercise. Left ventricular volume index, stroke volume index (LVSVI), left atrial end-systolic volume index (LAESVI), left atrial end-diastolic volume index (LAEDVI), and left atrial emptying fraction (LAEF), reservoir fraction, and conduit fraction were analyzed. The LVSVI increased with low exercise but did not increase further with peak exercise; cardiac output increased through the agency of heart rate. The LAESVI and LAEDVI decreased and the LAEF increased with exercise. As a result, the LA reservoir volume index was static throughout exercise. The reservoir fraction decreased from 46% at rest to 40% with low exercise (P < 0.001) in association with increased LVSVI and remained similar at peak exercise. The conduit volume index increased from 20 mL/m2 at rest to 24 mL/m2 at low exercise and stayed the same at peak exercise. Similarly, the conduit fraction increased from 54% at rest to 60% at low exercise (P < 0.001) and did not change further with peak exercise. Although atrial function increased with exercise, the major contribution to the augmentation of LV stroke volume is LA conduit fraction, a marker of active ventricular relaxation. Furthermore, the major determinant of raising cardiac output during high-level exercise is heart rate.NEW & NOTEWORTHY Diseases of the left atrium (LA) are major sources of disability (e.g., strokes and fatigue), but its exercise physiology has been unstudied. Such knowledge may allow early recognition of disease and suggest therapies. We show that in normal subjects, low-level exercise decreases LA volume and increases its ejection fraction. However, these changes offset each other volumetrically, and the contribution to LV filling from a full to an empty LA (reservoir function) is static. Higher levels of exercise do not change LA reservoir contribution. Blood flowing directly from the pulmonary vein to LV (conduit flow) impelled by augmented LV active relaxation (suction) is the major source of a modest increase in LV stroke volume. The major source of increased cardiac output with exercise is heart rate. During all stages of exercise, the LA works hard but only to keep up. We believe that our findings provide an additional set of benchmarks through which to quantitate LA pathology and gauge its progression.

Potential Biomarkers in Atrial Fibrillation: Insight Into Their Clinical Significance.

ABSTRACT: In risk-stratifying patients with atrial fibrillation (AF), physicians rely heavily on clinical parameters that provide risk scores and determine treatment strategies. There has been increasing research on potential biomarkers in the blood that could more accurately determine both risk of complications in AF and risk of incidence of AF. This review highlights the clinical significance of 5 novel biomarkers that have been shown to be linked to AF. These biomarkers are carbohydrate antigen 125, galectin-3, growth differentiation factor-15, a member of the interleukin 1 receptor family, IL1RL1 (ST2), and N-terminal pro B-type natriuretic peptide.

Atrial Reservoir Strain is Associated with Decreased Cardiac Index and Adverse Outcomes Post Fontan Operation.

Fontan patients rely on atrial function for diastolic filling and to augment cardiac output. Emerging data suggests that diminished atrial function is predictive of poor outcomes in adults but studies evaluating the association between atrial mechanics in Fontan patients and outcomes are lacking. We sought to assess atrial function in Fontan patients using speckle tracking echocardiography to determine whether atrial function is associated with invasive hemodynamics and clinical outcomes. Single-center review of Fontan patients receiving both catheterization and echocardiogram from 2012-2017. Atrial reservoir, conduit and pump global longitudinal strain and strain rate were assessed by speckle tracking echocardiography. The primary outcome was a composite of all adverse clinical outcomes including cardiac hospitalizations, transplant and death. Eighty-three Fontan patients at a median age of 14.2 years (IQR 8.6, 21.7) at time of echocardiogram were included. Increased atrial reservoir strain (p = 0.04), atrial emptying fraction (p = 0.04) and atrial fractional area change (p = 0.04), were associated with higher cardiac index at baseline. There were no associations between atrial strain and systemic ventricular end diastolic pressure (EDP) at catheterization. Reservoir strain was inversely associated with the composite clinical outcome on multivariable Cox proportional hazard analysis (HR 0.96, p = 0.03). Reduced atrial function is associated with reduced cardiac index, but is not directly associated with ventricular EDP in Fontan patients. Reservoir strain is associated with an excess of adverse clinical outcomes in Fontan patients.

Ventricular and atrial functions assessed by speckle-tracking echocardiography in patients with human immunodeficiency virus.

PURPOSE: Antiretroviral therapy (ART) has dramatically changed the clinical manifestation of human immunodeficiency virus (HIV) associated cardiomyopathy from severe left ventricular (LV) systolic dysfunction to a pattern of subclinical cardiac dysfunction. The aim of this study was to evaluate by speckle tracking echocardiography (STE) LV, right ventricular (RV), and biatrial functions in HIV-infected patients under different ART combinations. METHODS: We consecutively included 128 HIV-infected patients (mean age 44.2 ± 10.1 years, 110 males) and 100 controls (mean age 42.1 ± 9.4 years, 83 males). Ventricular and atrial functions were assessed by both conventional and STE. RESULTS: Although there was not any significant difference in conventional echocardiographic variables, HIV-infected patients had significantly lower LV global longitudinal strain (GLS), RV GLS, left atrial (LA) reservoir and conduit strain, and right atrial conduit strain. HIV patients receiving integrase strand transfer inhibitors and protease inhibitors (PI) had significantly lower LV GLS and LA conduit strain, while patients receiving non-nucleoside reverse transcriptase inhibitors and PI had significantly lower RV GLS than controls. CD4 count at the time of echocardiography was strongly correlated with LV GLS (r = .619, P < .001) and RV GLS (r = .606, P < .001). CONCLUSION: Biventricular and atrial functions are subclinically impaired in HIV-infected patients. ART regimen may also affect myocardial functions.

Effect of atrial artificial electrical stimulation on depolarization and repolarization and hemodynamics of the heart ventricle in rainbow trout Oncorhynchus mykiss.

The spatial-temporal organization of the activation, repolarization and hemodynamics of the heart ventricle in rainbow trout, Oncorhynchus mykiss, adapted to a temperature of 5-7 °C, were studied from the normal sinus rhythm (21.6 ± 4.9 bpm) to the highest possible heart rhythm (HR) (60 bpm), during which deterioration of the contractile activity of the myocardium occurred. Regardless of the HR, the main pattern of excitation of the heart ventricle was the movement of the depolarization wave from the dorsal areas of the base in the base-apical and ventral directions with the capture of the entire thickness of the walls, with a slight difference in the time of activation of the subendocardium compared to the subepicardium. The increase in HR above the sinus rhythm caused significant shortening of local repolarization durations in all areas and layers (endocardial, intramural and subepicardial) of the heart ventricle. Changes in local durations of repolarization led to an increase in the heterogeneity of repolarization of the ventricular myocardium; as a result, a deterioration of its contractility was observed. In relation to the sinus rhythm, the maximal systolic pressure in the heart ventricle decreased, the diastolic and end-diastolic pressure increased, and the maximum rates of pressure rise and fall decreased. In rainbow trout adapted to a temperature of 5-7 °C at sinus rhythm, the pumping function of the heart was probably within the upper limit of the physiological norm, and a further increase in the heart rate led to a decline in myocardial contractility.

A compartmentalized mathematical model of mouse atrial myocytes.

Various experimental mouse models are extensively used to research human diseases, including atrial fibrillation, the most common cardiac rhythm disorder. Despite this, there are no comprehensive mathematical models that describe the complex behavior of the action potential and [Ca2+]i transients in mouse atrial myocytes. Here, we develop a novel compartmentalized mathematical model of mouse atrial myocytes that combines the action potential, [Ca2+]i dynamics, and ß-adrenergic signaling cascade for a subpopulation of right atrial myocytes with developed transverse-axial tubule system. The model consists of three compartments related to ß-adrenergic signaling (caveolae, extracaveolae, and cytosol) and employs local control of Ca2+ release. It also simulates ionic mechanisms of action potential generation and describes atrial-specific Ca2+ handling as well as frequency dependences of the action potential and [Ca2+]i transients. The model showed that the T-type Ca2+ current significantly affects the later stage of the action potential, with little effect on [Ca2+]i transients. The block of the small-conductance Ca2+-activated K+ current leads to a prolongation of the action potential at high intracellular Ca2+. Simulation results obtained from the atrial model cells were compared with those from ventricular myocytes. The developed model represents a useful tool to study complex electrical properties in the mouse atria and could be applied to enhance the understanding of atrial physiology and arrhythmogenesis.NEW & NOTEWORTHY A new compartmentalized mathematical model of mouse right atrial myocytes was developed. The model simulated action potential and Ca2+ dynamics at baseline and after stimulation of the ß-adrenergic signaling system. Simulations showed that the T-type Ca2+ current markedly prolonged the later stage of atrial action potential repolarization, with a minor effect on [Ca2+]i transients. The small-conductance Ca2+-activated K+ current block resulted in prolongation of the action potential only at the relatively high intracellular Ca2+.

Cellular and mitochondrial mechanisms of atrial fibrillation.

The molecular mechanisms underlying atrial fibrillation (AF), the most common form of arrhythmia, are poorly understood and therefore target-specific treatment options remain an unmet clinical need. Excitation-contraction coupling in cardiac myocytes requires high amounts of adenosine triphosphate (ATP), which is replenished by oxidative phosphorylation in mitochondria. Calcium (Ca2+) is a key regulator of mitochondrial function by stimulating the Krebs cycle, which produces nicotinamide adenine dinucleotide for ATP production at the electron transport chain and nicotinamide adenine dinucleotide phosphate for the elimination of reactive oxygen species (ROS). While it is now well established that mitochondrial dysfunction plays an important role in the pathophysiology of heart failure, this has been less investigated in atrial myocytes in AF. Considering the high prevalence of AF, investigating the role of mitochondria in this disease may guide the path towards new therapeutic targets. In this review, we discuss the importance of mitochondrial Ca2+ handling in regulating ATP production and mitochondrial ROS emission and how alterations, particularly in these aspects of mitochondrial activity, may play a role in AF. In addition to describing research advances, we highlight areas in which further studies are required to elucidate the role of mitochondria in AF.

Impact of atrial programmed electrical stimulation techniques on unipolar electrogram morphology.

INTRODUCTION: Intra-atrial conduction abnormalities are associated with the development of atrial fibrillation (AF) and cause morphological changes of the unipolar atrial electrogram (U-AEGM). This study examined the impact of different atrial programmed electrical stimulation (APES) protocols on U-AEGM morphology to identify the most optimal APES protocol provoking conduction abnormalities. METHODS: APES techniques (14 protocols) were applied in 30 patients referred for an electrophysiology study, consisting of fixed rate, extra, and decremental stimuli at different frequencies. U-AEGM morphologies including width, amplitude, and fractionation for patients without (control group) and with a history of AF (AF group) were examined during APES. In addition, sinus rhythm (SR) U-AEGMs preceding different APES protocols were compared to evaluate the morphology stability over time. RESULTS: U-AEGM morphologies during SR before the APES protocols were comparable (all P > .396). Atrial refractoriness was longer in the AF group compared to the control group (298 ± 48 vs 255 ± 33 ms; P ≤ .020), but did not differ between AF patients with and without amiodarone therapy (278 ± 48 vs 311 ± 40 ms; P ≥ .126). Compared to the initial SR morphology, U-AEGM width, amplitude, and fractionation changed significantly during the 14 different APES protocols, particularly in the AF group. In both groups, U-AEGM changes in morphology were most pronounced during fixed-rate stimulation with extra stimuli (8S1-S2 = 400-250 ms). CONCLUSION: APES results in significant changes in U-AEGM morphology, including width, amplitude, and fractionation. The impact of APES differed between APES sequence and between patients with and without AF. These findings suggest that APES could be useful to identify AF-related conduction abnormalities in the individual patient.

The role of atrial sensing for new-onset atrial arrhythmias diagnosis and management in single-chamber implantable cardioverter-defibrillator recipients: Results from the THINGS registry.

INTRODUCTION: Atrial tachycardia/fibrillation (AT/AF) episodes are common in implantable cardioverter-defibrillator (ICD) recipients and can be undetected by standard single-chamber devices. This study aims to explore whether a single-lead ICD with an atrial dipole (ICD DX; BIOTRONIK SE & Co, Berlin, Germany) could improve the AT/AF diagnosis and management as compared to standard ICD (ICD VR). METHODS AND RESULTS: We selected patients without AT/AF history from the THINGS registry which included consecutive patients implanted with ICD for standard indications. The ICD VR and the ICD DX groups included 236 (62.8%) and 140 (37.2%) patients, respectively, and had no significant differences in baseline characteristics. During a median follow-up of 27 months, there were 7 AT/AF diagnoses in the ICD VR and 18 in the ICD DX group. The 2-year incidence of AT/AF diagnosis was 3.6% (95% confidence interval [CI]: 1.6%-9.6%) for the ICD VR and 11.4% (95% CI: 6.8%-18.9%) for the ICD DX group (adjusted hazard ratio [HR]: 3.85 [95% CI: 1.58-9.41]; P = .003). Initiation of oral anticoagulation (OAC) due to AT/AF diagnosis was reported in 15 patients. The 2-year incidence of OAC onset was 3.6% (95% CI: 1.6%-7.8%) for the ICD VR and 6.3% (95% CI: 3.0%-12.7%) for ICD DX group (adjusted HR: 1.99 [95% CI: 0.72-5.56]; P = .184). CONCLUSION: We observed that atrial sensing capability in single-chamber ICD patients without evidence of atrial arrhythmias at implant is associated with a greater likelihood of detecting AT/AF episodes. The management of these diagnosed arrhythmias often led to clinical interventions, mainly represented by initiation of OAC therapy.

Late Sodium Current in Atrial Cardiomyocytes Contributes to the Induced and Spontaneous Atrial Fibrillation in Rabbit Hearts.

Increased late sodium current (INa) induces long QT syndrome 3 with increased risk of atrial fibrillation (AF). The role of atrial late INa in the induction of AF and in the treatment of AF was determined in this study. AF parameters were measured in isolated rabbit hearts exposed to late INa enhancer and inhibitors. Late INa from isolated atrial and ventricular myocytes were measured using whole-cell patch-clamp techniques. We found that induced-AF by programmed S1S2 stimulation and spontaneous episodes of AF were recorded in hearts exposed to either low (0.1-3 nM) or high (3-10 nM) concentrations of ATX-II (n = 10). Prolongations in atrial monophasic action potential duration at 90% completion of repolarization and effective refractory period by ATX-II (0.1-15 nM) were greater in hearts paced at slow than at fast rates (n = 5-10, P < 0.05). Both endogenous and ATX-II-enhanced late INa density were greater in atrial than that in ventricular myocytes (n = 9 and 8, P < 0.05). Eleclazine and ranolazine reduced AF window and AF burden in association with the inhibition of both endogenous and enhanced atrial late INa with half maximal inhibitory concentrations (IC50) of 1.14 and 9.78, and 0.94 and 8.31 µM, respectively. The IC50s for eleclazine and ranolazine to inhibit peak INa were 20.67 and 101.79 µM, respectively, in atrial myocytes. In conclusion, enhanced late INa in atrial myocytes increases the susceptibility for AF. Inhibition of either endogenous or enhanced late INa, with increased atrial potency of drugs is feasible for the treatment of AF.

Gaussian process manifold interpolation for probabilistic atrial activation maps and uncertain conduction velocity.

In patients with atrial fibrillation, local activation time (LAT) maps are routinely used for characterizing patient pathophysiology. The gradient of LAT maps can be used to calculate conduction velocity (CV), which directly relates to material conductivity and may provide an important measure of atrial substrate properties. Including uncertainty in CV calculations would help with interpreting the reliability of these measurements. Here, we build upon a recent insight into reduced-rank Gaussian processes (GPs) to perform probabilistic interpolation of uncertain LAT directly on human atrial manifolds. Our Gaussian process manifold interpolation (GPMI) method accounts for the topology of the atrium, and allows for calculation of statistics for predicted CV. We demonstrate our method on two clinical cases, and perform validation against a simulated ground truth. CV uncertainty depends on data density, wave propagation direction and CV magnitude. GPMI is suitable for probabilistic interpolation of other uncertain quantities on non-Euclidean manifolds. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.

Adaptation of ventricular repolarization duration and dispersion during changes in heart rate induced by atrial stimulation.

BACKGROUND: The duration of ventricular repolarization (VR) and its spatial and temporal heterogeneity are central elements in arrhythmogenesis. We studied the adaptation of VR duration and dispersion and their relationship in healthy human subjects during atrial pacing. METHODS: Patients 20-50 years of age who were scheduled for ablation of supraventricular tachycardia without preexcitation but otherwise healthy were eligible. Vectorcardiography recordings with Frank leads were used for data collection. Incremental atrial pacing from a coronary sinus electrode was performed by decrements of 10ms/cycle from just above sinus rate, and then kept at a fixed heart rate (HR) just below the Wenckebach rate for ≥5min and then stopped. VR duration was measured as QT and VR dispersion as T area, T amplitude and ventricular gradient. The primary measure (T90 End) was the time to reach 90% change from baseline to the steady state value during and after pacing. RESULTS: A complete study protocol was accomplished in 9 individuals (6 women). VR duration displayed a monophasic adaptation during HR acceleration lasting on average 20s. The median (Q1-Q3) T90 End for QT was 85s (51-104), a delay by a factor >4. All dispersion measures displayed a tri-phasic response pattern during HR acceleration and T90 End was 3-5 times shorter than for VR duration. CONCLUSIONS: Even during close to "physiological" conditions, complex and differing response patterns in VR duration and dispersion measures followed changes in HR. Extended knowledge about these responses in disease conditions might assist in risk evaluation and finding therapeutic alternatives.