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Catheter ablation of ventricular arrhythmias (VAs) arising from the left ventricle`s (LV) papillary muscles (PM) is challenging. In this study we present results of catheter ablation using multiple energy sources and image-based approaches.

The effects of bucumolol (BUC), nadolol (NAD) and nifenalol (NIF) on contractile forces and on action potentials (APs) were investigated in isolated guinea pig atrial and papillary muscles, respectively. Log 1/ED40 values for the negative inotropic effects of these drugs were 0.097, 10 and 0.74 mmol/l in this order. BUC (50 mumol/l), NAD (0.5 mmol/l) and NIF (0.2 mmol/l) produced about 60, 20 and 20% reduction of Vmax at 1 Hz. The frequency-dependent reductions at these and higher concentrations were greatest for BUC, intermediate for NAD and least for NIF. These potencies at certain frequencies were, as a whole, consistent with log P-potency relationship established in our previous papers (Harada et al. 1981; Ban et al. 1985). The reductions of Vmax in APs in response to premature stimuli during basic stimuli at the rate of 0.25 or 0.027 Hz decayed exponentially during diastolic intervals (DI). The time constants of these decay process (tau) estimated by linear and nonlinear regression analyses and by eye were 12.2-9.6 s for BUC (50-100 mumol/l) and 2.9-4.8 s for NAD (1-2 mmol/l) and 57-87 ms for NIF (0.2-1 mmol/l). In terms of the molecular weight (MW)-log tau relationship (Ban et al. 1985), these tau values are within the 95% fiducial limit for BUC and NAD and deviated from the lower fiducial limit for NIF. The frequency-dependent reductions of Vmax by these drugs were explained in terms of a function of tau and the intercept Ao. Based on the study made by Cohen et al.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficient pumping of the healthy left ventricle (LV) requires heterogeneities in mechanical function of individual cardiomyocytes (CM). Deformation of sub-endocardial (Endo) tissue is greater than that of sub-epicardial (Epi) regions. Papillary muscles (PM), often considered to be part of Endo tissue, show lower beat-by-beat length variation than Epi (or Endo) regions, even though they contribute to the shift in atrio-ventricular valve plane, which is essential for LV pump function. Thus far, no comparative assessment of CM mechanics for PM and LV free wall has been published. Here, we investigate contractility and cytosolic calcium concentration ([Ca2+]c) transients in rabbit single CM, freshly isolated from PM, Endo and Epi regions of the LV (free wall tissue was further subdivided into near-basal [Base], equatorial [Centre], and near-apical [Apex] parts). Functional parameters were measured in the absence of external mechanical loads (non-loaded), or during afterloaded (auxotonic) CM contractions, initiated from different levels of preload (diastolic axial stretch), using the carbon fibre technique. We note significant differences in time-course and amplitudes of sarcomere shortening between PM, Endo and Epi CM. In non-loaded CM, sarcomere shortening between regions compares as follows: Endo > Epi and Endo > PM. During afterloaded contractions, the slope of auxotonic tension-length relation and the Frank-Starling gain index (preload-dependent increase in tension and shortening) follow the sequence of Endo > Epi > PM. In terms of apico-basal gradients, time-to-peak sarcomere shortening was greater in Apex compared to Centre and Base in non-loaded CM only. Thus, CM from PM show the least pronounced preload-dependent activation of force across the LV regions assessed, while CM from Endo regions show the strongest response. This is in keeping with prior in situ observations on the smaller extent of PM shortening and their thus lower functional requirement for sensitivity to preload, compared to LV free wall. The here identified regional differences in cellular Frank-Starling responses illustrate the extent to which CM mechanical responses appear to be in keeping with in situ differences in mechanical demand.

The cardiac work-loop technique closely mimics the intrinsic in vivo movement and characteristics of cardiac muscle function. In this study, six known inotropes were profiled using the work-loop technique to evaluate the potential of this method to predict inotropy. Papillary muscles from male Sprague-Dawley rats were mounted onto an organ bath perfused with Krebs-Henseleit buffer. Following optimisation, work-loop contractions were performed that included an initial stabilisation period followed by vehicle control or drug administration. Six known inotropes were tested: digoxin, dobutamine, isoprenaline, flecainide, verapamil and atenolol. Muscle performance was evaluated by calculating power output during work-loop contraction. Digoxin, dobutamine and isoprenaline caused a significant increase in power output of muscles when compared to vehicle control. Flecainide, verapamil and atenolol significantly reduced power output of muscles. These changes in power output were reflected in alterations in work loop shapes. This is the first study in which changes in work-loop shape detailing for example the activation, shortening or passive re-lengthening have been linked to the mechanism of action of a compound. This study has demonstrated that the work-loop technique can provide an important novel method with which to assess detailed mechanisms of drug-induced effects on cardiac muscle contractility.

Sphingolipid deposition in Fabry disease causes left ventricular (LV) hypertrophy, of which the accurate assessment is essential. Cardiovascular magnetic resonance (CMR) has been proposed as the gold standard. However, there is debate in the literature as to whether papillary muscles and trabeculations (P&T) should be included in LV mass (LVM).

The main pathophysiological factor of chronic ischemic mitral regurgitation (MR) is the outward displacement of the papillary muscles (PMs) leading to leaflet tethering. For this reason, papillary muscle intervention (PMI) in combination with mitral ring annuloplasty (MRA) has recently been introduced into clinical practice to correct this displacement, and to reduce the recurrence of regurgitation.

While the reductionist approach has been fruitful in understanding the molecular basis of muscle function, intact excitable muscle preparations are still important as experimental model systems. We present here methods that are useful for preparing cardiac papillary muscle and cardiac slices, which represent macroscopic experimental model systems with fully intact intercellular and intracellular structures. The maintenance of these in vivo structures for experimentation in vitro have made these model systems especially useful for testing the functional effects of protein mutations and pharmaceutical candidates. We provide solutions recipes for dissection and recording, instructions for removing and preparing the cardiac papillary muscles, as well as instruction for preparing cardiac slices. These instructions are suitable for beginning experimentalists but may be useful for veteran muscle physiologists hoping to reacquaint themselves with macroscopic functional analyses.

The use of frozen and cryo-sectioned cardiac muscle preparations, introduced recently by (Feng & Jin, 2020), offers promising advantages of easy transport and exchange of muscle samples among collaborating laboratories. In this report, we examined integrity of such preparation by studying tension transients in response to sinusoidal length changes and following concomitant amplitude and phase shift in tension time courses at varying frequencies. We used sections with 70 μm thickness, isolated fiber preparations, and studied cross-bridge (CB) kinetics: we activated the preparations with saturating Ca2+, and varying concentrations of ATP and phosphate (Pi). Our experiments have demonstrated that this preparation has the normal active tension and elementary steps of the CB cycle. Furthermore, we investigated the effect of Ca2+ on the rate constants and found that the rate constant r4 of the force generation step is proportionate to [Ca2+] when it is <5 μM. This observation suggests that the activation mechanism can be described by a simple second order reaction. As expected, we found that magnitude parameters including tension and stiffness are related to [Ca2+] by the Hill equation with cooperativity of 4-5, consistent to the fact that Ca2+ activation mechanisms involve cooperative multimolecular interactions. Our results are consistent with a long-held hypothesis that process C (phase 2 of step analysis) represents the CB detachment step, and process B (phase 3) represents the force generation step. In this report, we further found that constant H may also represent work performance step. Our experiments have demonstrated excellent CB kinetics with reduced noise and well-defined two exponentials, which are better than skinned fibers, and easier to handle and study than single myofibrils.

Historic studies with sodium ion (Na+ ) micropipettes and first-generation fluorescent probes suggested that an increase in heart rate results in higher intracellular Na+ -levels. Using a dual fluorescence indicator approach, we simultaneously assessed the dynamic changes in intracellular Na+ and calcium (Ca2+ ) with measures of force development in isolated excitable myocardial strip preparations from rat and human left ventricular myocardium at different stimulation rates and modeled the Na+ -effects on the sodium-calcium exchanger (NCX). To gain further insight into the effects of heart rate on intracellular Na+ -regulation and sodium/potassium ATPase (NKA) function, Na+ , and potassium ion (K+ ) levels were assessed in the coronary effluent (CE) of paced human subjects. Increasing the stimulation rate from 60/min to 180/min led to a transient Na+ -peak followed by a lower Na+ -level, whereas the return to 60/min had the opposite effect leading to a transient Na+ -trough followed by a higher Na+ -level. The presence of the Na+ -peak and trough suggests a delayed regulation of NKA activity in response to changes in heart rate. This was clinically confirmed in the pacing study where CE-K+ levels were raised above steady-state levels with rapid pacing and reduced after pacing cessation. Despite an initial Na+ peak that is due to a delayed increase in NKA activity, an increase in heart rate was associated with lower, and not higher, Na+ -levels in the myocardium. The dynamic changes in Na+ unveil the adaptive role of NKA to maintain Na+ and K+ -gradients that preserve membrane potential and cellular Ca2+ -hemostasis.

The 2016 European Society of Cardiology Heart Failure Guidelines defined a new category: heart failure with mid-range ejection fraction (HFmrEF) of 40-49%. This new category was highlighted as having limited evidence and research was advocated into underlying characteristics, pathophysiology, and diagnosis. We used multi-parametric cardiovascular magnetic resonance (CMR) to define the cardiac phenotype of presumed non-ischaemic HFmrEF.

To analyze alterations in left ventricular (LV) myocardial T1 times in patients with pulmonary hypertension (PH) and to investigate their associations with ventricular function, mass, geometry and hemodynamics.

Interstitial myocardial fibrosis is one of the factors responsible for dysfunction of the heart. However, how interstitial fibrosis affects cardiac function and excitation-contraction coupling (E-C coupling) has not yet been clarified. We developed an animal model of right ventricular (RV) hypertrophy with fibrosis by pulmonary artery (PA) banding in rats. Two, four, and six weeks after the PA-banding operation, the tension and intracellular Ca2+ concentration of RV papillary muscles were simultaneously measured (n = 33). The PA-banding rats were clearly divided into two groups by the presence or absence of apparent interstitial fibrosis in the papillary muscles: F+ or F- group, respectively. The papillary muscle diameter and size of myocytes were almost identical between F+ and F-, although the RV free wall weight was heavier in F+ than in F-. F+ papillary muscles exhibited higher stiffness, lower active tension, and lower Ca2+ responsiveness compared with Sham and F- papillary muscles. In addition, we found that the time to peak Ca2+ had the highest correlation coefficient to percent of fibrosis among other parameters, such as RV weight and active tension of papillary muscles. The phosphorylation level of troponin I in F+ was significantly higher than that in Sham and F-, which supports the idea of lower Ca2+ responsiveness in F+. We also found that connexin 43 in F+ was sparse and disorganized in the intercalated disk area where interstitial fibrosis strongly developed. In the present study, the RV papillary muscles obtained from the PA-banding rats enabled us to directly investigate the relationship between fibrosis and cardiac dysfunction, the impairment of E-C coupling in particular. Our results suggest that interstitial fibrosis worsens cardiac function due to 1) the decrease in Ca2+ responsiveness and 2) the asynchronous activation of each cardiac myocyte in the fibrotic preparation due to sparse cell-to-cell communication.

The hypertensive deoxy-corticosterone acetate (DOCA)-salt-treated pig (hereafter, DOCA pig) was recently introduced as large animal model for early-stage heart failure with preserved ejection fraction (HFpEF). The aim of the present study was to evaluate cardiovascular magnetic resonance (CMR) of DOCA pigs and weight-matched control pigs to characterize ventricular, atrial and myocardial structure and function of this phenotype model.

Invaginations of the cellular membrane called t-tubules are essential for maintaining efficient excitation-contraction coupling in ventricular cardiomyocytes. Disruption of t-tubule structure during heart failure has been linked to dyssynchronous, slowed Ca(2+) release and reduced power of the heartbeat. The underlying mechanism is, however, unknown. We presently investigated whether elevated ventricular wall stress triggers remodelling of t-tubule structure and function.

Transgenic (TG) Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) δ(C) mice develop systolic heart failure (HF). CaMKII regulates intracellular Ca(2+) handling proteins as well as sarcolemmal Na(+) channels. We hypothesized that CaMKII also contributes to diastolic dysfunction and arrhythmias via augmentation of the late Na(+) current (late I(Na)) in early HF (8-week-old TG mice). Echocardiography revealed severe diastolic dysfunction in addition to decreased systolic ejection fraction. Premature arrhythmogenic contractions (PACs) in isolated isometrically twitching papillary muscles only occurred in TG preparations (5 vs. 0, P < 0.05) which could be completely terminated when treated with the late I(Na) inhibitor ranolazine (Ran, 5 μmol/L). Force-frequency relationships revealed significantly reduced twitch force amplitudes in TG papillary muscles. Most importantly, diastolic tension increased with raising frequencies to a greater extent in TG papillary muscles compared to WT specimen (at 10 Hz: 3.7 ± 0.4 vs. 2.5 ± 0.3 mN/mm²; P < 0.05). Addition of Ran improved diastolic dysfunction to 2.1 ± 0.2 mN/mm² (at 10 Hz; P < 0.05) without negative inotropic effects. Mechanistically, the late I(Na) was markedly elevated in myocytes isolated from TG mice and could be completely reversed by Ran. In conclusion, our results show for the first time that TG CaMKIIδ(C) overexpression induces diastolic dysfunction and arrhythmogenic triggers possibly via an enhanced late I(Na). Inhibition of elevated late I(Na) had beneficial effects on arrhythmias as well as diastolic function in papillary muscles from CaMKIIδ(C) TG mice. Thus, late I(Na) inhibition appears to be a promising option for diastolic dysfunction and arrhythmias in HF where CaMKII is found to be increased.

An intriguing difference between vertebrate skeletal and cardiac muscles is that the lengths of the thin filaments are constant in the former but variable in the latter. The thick filaments have constant lengths in both types of muscles. The contractile behaviour of a muscle is affected by the lengths of both types of filaments as the tension generated during contraction depends on the amount of filament overlap. To understand the behaviour of cardiac muscle, it is important to know the distribution of the thin filament lengths. The previous detailed analysis by Robinson and Winegrad used serial transverse sections to determine the lengths of the thin filaments. However, the precision, set by the 100 nm section thickness, was low. Here, we have used electron tomography to produce 3D images of rat and mouse cardiac muscles in which we can actually see individual thin filaments up to the free ends and see that these free ends have variable locations. For comparison, we also measure the thin filament lengths in skeletal muscle (frog sartorius).

Patients suffering from heart failure and left bundle branch block show electrical ventricular dyssynchrony causing an abnormal blood pumping. Cardiac resynchronization therapy (CRT) is recommended for these patients. Patients with positive therapy response normally present QRS shortening and an increased left ventricle (LV) ejection fraction. However, around one third do not respond favorably. Therefore, optimal location of pacing leads, timing delays between leads and/or choosing related biomarkers is crucial to achieve the best possible degree of ventricular synchrony during CRT application. In this study, computational modeling is used to predict the optimal location and delay of pacing leads to improve CRT response. We use a 3D electrophysiological computational model of the heart and torso to get insight into the changes in the activation patterns obtained when the heart is paced from different regions and for different atrioventricular and interventricular delays. The model represents a heart with left bundle branch block and heart failure, and allows a detailed and accurate analysis of the electrical changes observed simultaneously in the myocardium and in the QRS complex computed in the precordial leads. Computational simulations were performed using a modified version of the O'Hara et al. action potential model, the most recent mathematical model developed for human ventricular electrophysiology. The optimal location for the pacing leads was determined by QRS maximal reduction. Additionally, the influence of Purkinje system on CRT response was assessed and correlation analysis between several parameters of the QRS was made. Simulation results showed that the right ventricle (RV) upper septum near the outflow tract is an alternative location to the RV apical lead. Furthermore, LV endocardial pacing provided better results as compared to epicardial stimulation. Finally, the time to reach the 90% of the QRS area was a good predictor of the instant at which 90% of the ventricular tissue was activated. Thus, the time to reach the 90% of the QRS area is suggested as an additional index to assess CRT effectiveness to improve biventricular synchrony.

Arrhythmic mitral valve prolapse (MVP) is characterized by myxomatous leaflets and left ventricular (LV) fibrosis of papillary muscles and inferobasal wall. We searched for morphofunctional abnormalities of the mitral valve that could explain a regional mechanical myocardial stretch.

Background Because systemic inflammation and endothelial dysfunction lead to heart failure with preserved ejection fraction, we characterized plasma levels of inflammatory and cardiac remodeling biomarkers in patients with Fabry disease ( FD ). Methods and Results Plasma biomarkers were studied in multicenter cohorts of patients with FD (n=68) and healthy controls (n=40). Plasma levels of the following markers of inflammation and cardiac remodeling were determined: tumor necrosis factor ( TNF ), TNF receptor 1 ( TNFR 1) and 2 ( TNFR 2), interleukin-6, matrix metalloprotease-2 ( MMP -2), MMP -8, MMP -9, galectin-1, galectin-3, B-type natriuretic peptide ( BNP ), midregional pro-atrial natriuretic peptide ( MR -pro ANP ), and globotriaosylsphingosine. Clinical profile, cardiac magnetic resonance imaging, and echocardiogram were reviewed and correlated with biomarkers. Patients with FD had elevated plasma levels of BNP , MR -pro ANP , MMP -2, MMP -9, TNF , TNFR 1, TNFR 2, interleukin-6, galectin-1, globotriaosylsphingosine, and analogues. Plasma TNFR 2, TNF , interleukin-6, MMP -2, and globotriaosylsphingosine were elevated in FD patients with left ventricular hypertrophy, whereas diastolic dysfunction correlated with higher BNP , MR -pro ANP , and MMP -2 levels. Patients with late gadolinium enhancement on cardiac magnetic resonance imaging had greater levels of BNP , MR -pro ANP , TNFR 1, TNFR 2, and MMP -2. Plasma BNP , MR -pro ANP , MMP -2, MMP -8, TNF , TNFR 1, TNFR 2, galectin-1, and galectin-3 were elevated in patients with renal dysfunction. Patients undergoing enzyme replacement therapy who have more severe disease had higher MMP -2, TNF , TNFR 1, TNFR 2, and globotriaosylsphingosine analogue levels. Conclusions Inflammatory and cardiac remodeling biomarkers are elevated in FD patients and correlate with disease progression. These features are consistent with a phenotype dominated by heart failure with preserved ejection fraction and suggest a key pathogenic role of systemic inflammation in FD .