Postextrasystolic Potentiation Research Articles

Unraveling the pathogenesis of novel ANKRD1 missense mutation causing familial dilated cardiomyopathy using human-induced pluripotent stem cells derived cardiomyocytes

Abstract Introduction Familial dilated cardiomyopathy(f-DCM) can be caused by mutations in 30 different genes encoding sarcomeric, cytoskeletal, mechanotransducers and transcription factors. One of the genes ANKRD1 encode Cardiac ankyrin repeat protein (CARP) which is involved in the mechanosensory unit located on the I-band of the sarcomere. Here we demonstrate a novel mutation in ANKRD1 gene causing f-DCM, and the usage of human-induced pluripotent(hiPSC) technology unraveling the pathogenesis of the disease. Purpose of the study: 1) Establishing patient specific hiPSC-derived cardiomyocytes from a family harboring a mutation in ANKRD1 gene causing f-DCM; 2) Phenotypical assessment of the morphological and ultrastructural properties of the diseased cells upon CARP activation; 3) Functional assessment of the 3 component of excitation-contraction coupling at the single-cell and tissue level. Methods and Results Patient-specific hiPSC were generated from a family harboring missense mutation in the ANKRD1 gene, with a substitution of the amino acid arginine to cysteine at position 182 of the Cardiac ankyrin repeat protein (CARP). ANKRD1-mut hiPSC were differentiated into cardiomyocytes and later matured using hormonal treatment. Morphological assessment using immunofluorescence(IF) techniques revealed that ANKRD1-mut hiPSC-CMs demonstrate an attenuated response to hypertrophy (upon Angiotensin-2 and Phenylephrine treatment). In addition ANKRD1-mut hiPSC-CMs displayed a higher cellular death rate upon increasing substrate stiffness and starvation. Electrophysiological assessment of the ANKRD1-mut cardiac tissues exhibit no alternations in action potential durations and conduction velocities while assessment of calcium transients demonstrated slower kinetics. In addition forces were quantified at the single-cell and tissue level , and demonstrated reduced active tension values and abnormal post-extrasystolic potentiation, while only single-cell experiments have demonstrated decreased passive tensions. These phenotypical alternations might be attributed to decreased nuclear translocation of CARP upon phenylephrine treatment as detected in IF experiments. Conclusion Novel mutation in ANKRD1 were found and validated to be causing f-DCM, by revealing phenotypical alternation using hiPSC-CM technology. Increased cellular death rate and impaired nuclear translocation of CARP might be the underlying causes of the morphological and contractile abnormalities detected in-vitro, leading to systolic dysfunction in the affected family.

Left ventricular remodeling in premature ventricular contraction-induced cardiomyopathy: Effect of coupling intervals and atrioventricular dissociation.

Left ventricular dyssynchrony (LVD) and postextrasystolic potentiation (PESP) associated with premature ventricular contractions (PVCs) may play a role in the development of premature ventricular contraction-induced cardiomyopathy (PVC-CM). Long-coupled (LC) PVCs have a greater LVD than short-coupled (SC) PVCs, whereas SC-PVCs have a stronger PESP than LC-PVCs. The purpose of this study was to compare SC-PVCs and LC-PVCs to evaluate the roles of LVD, PESP, and atrioventricular dissociation (AVD) in the development of PVC-CM. Thirty-six canines underwent pacemaker implantation to induce bigeminal right ventricular apical epicardial PVCs (50% burden) for 12 weeks. Telemetry assessed PVC burden and AVD. Animals were grouped as SC-PVC (coupling interval [CI] 200-220ms), LC-PVC (CI 330 ms), or sham (control). Echocardiographic changes, AVD, and hemodynamics were monitored for 12 weeks. PVC burden was similar between SC-PVC and LC-PVC groups but was statistically higher in the SC-PVC group (50% vs 47.5%; P = .028). After 12 weeks, left ventricular ejection fraction (LVEF) significantly decreased in both SC-PVC and LC-PVC groups (47.1% ± 1.4% and 45.5% ± 2%, respectively) compared to sham group (61% ± 1.6%; P <.001). Overall AVD was similar between SC-PVC and LC-PVC groups, and there was no significant correlation between AVD and reduction in LVEF at 12 weeks (r = 0.09, P = .5; and r = 0.06, P = .8, respectively). Additionally, both SC-PVC and LC-PVC groups experienced substantial declines in max and min dP/dt after 12 weeks compared to baseline. Neither PVC CI nor AVD played an independent role in the development or severity of PVC-CM. LVD and PESP make equal relative contributions to the development of PVC-CM.

Assessment of subtle cardiac dysfunction induced by premature ventricular contraction using two-dimensional strain echocardiography and the effects of successful ablation

Introduction and objectivesWe aimed to assess the effects of successful ablation on impaired left ventricular global longitudinal strain (LV-GLS) in patients with frequent premature ventricular contractions (PVCs). We also evaluated the potential risk factors of impaired LV-GLS. MethodsThirty-six consecutive patients without any structural heart disease, who were treated with radiofrequency (RF) ablation due to frequent PVCs, were included in the study. All patients were evaluated with standard transthoracic and two-dimensional speckle tracking echocardiography. ResultsMean LV-GLS before ablation was 17.3±3.7 and 20.5±2.6 after ablation; the difference was statistically significant (p<0.01). Patients were categorized into two groups: those with LV-GLS value >−16% and those ≤16%. Low PVC E flow/post-PVC E flow and PVC SV/post-PVC SV ratios were associated with impaired LV-GLS. ConclusionIn symptomatic patients with frequent PVCs and normal left ventricular ejection fraction, we observed significant improvement in LV-GLS value following successful RF ablation. Patients with impaired LV-GLS more often display non-ejecting PVCs and post-extrasystolic potentiation (PEP) compared to patients with normal LV-GLS.

Catheter-Induced Postextrasystolic Potentiation in the Assessment of Severity of Low-Gradient Aortic Valve Stenosis.

Deciphering which patients with low-gradient aortic valve disease have severe stenosis can be difficult. We aimed to correlate the postextrasystolic potentiation (PESP) with dobutamine stress echocardiography and multidetector computed tomography in patients with low-gradient aortic valve stenosis. Patients with an aortic valve area ≤1 cm2 and a mean gradient <40 mm Hg were included. Aortic valve stenosis severity was assessed by a core lab with dobutamine stress echocardiography, followed by a multidetector computed tomography aortic valve score if indeterminate. A premature ventricular contraction was induced by intentional catheter contact with the myocardium within the left ventricle. PESP was calculated as a percent change of pre-to-post mean gradient. Multidetector computed tomography was used to measure the aortic valve calcification score, and subsequently, aortic valve calcification density. Twenty-eight patients (age, 77±10 years; 19 female) were included. Dobutamine stress echocardiography increased mean gradient from baseline of 25±7 mm Hg to 36±11 mm Hg; pre-premature ventricular contraction mean gradient was 25±7 mm Hg and increased to post-premature ventricular contraction mean gradient of 32±10 mm Hg, representing a PESP of 24±11%. A ≥20% in PESP resulted in 100% sensitivity, 77% specificity, 83% positive predictive value, and 100% negative predictive value for diagnosing severe aortic valve stenosis. There was a significant correlation between PESP and projected aortic valve area and aortic valve calcification density (R=-0.64, P=0.0003; R=0.057, P=0.014, respectively). In patients with low-gradient aortic valve stenosis, catheter-induced premature ventricular contractions during cardiac catheterization causing ≥20% PESP has a 100% sensitivity for severe aortic valve stenosis. Validation of this 20% cutoff in larger groups with correlation to clinical end points is required.

Alterations of sarcoplasmic reticulum-mediated Ca2+ uptake in a model of premature ventricular contraction (PVC)-induced cardiomyopathy.

Premature ventricular contractions (PVCs) are the most frequent ventricular arrhythmias in the overall population. PVCs are known to acutely enhance contractility by the post-extrasystolic potentiation phenomenon, but over time persistent PVCs promote PVC-induced cardiomyopathy (PVC-CM), characterized by a reduction of the left ventricular (LV) ejection fraction. Ca2+ cycling in myocytes commands muscle contraction and in this process, SERCA2 leads the Ca2+ reuptake into the sarcoplasmic reticulum (SR) shaping cytosolic Ca2+ signal decay and muscle relaxation. Altered Ca2+ reuptake can contribute to the contractile dysfunction observed in PVC-CM. To better understand Ca2+ handling using our PVC-CM model (canines with 50% PVC burden for 12weeks), SR-Ca2+ reuptake was investigated by measuring Ca2+ dynamics and analyzing protein expression. Kinetic analysis of Ca2+ reuptake in electrically paced myocytes showed a ~ 21ms delay in PVC-CM compared to Sham in intact isolated myocytes, along with a ~ 13% reduction in SERCA2 activity assessed in permeabilized myocytes. Although these trends were not statistically significant between groups using hierarchical statistics, relaxation of myocytes following contraction was significantly slower in PVC-CM vs Sham myocytes. Western blot analyses indicate a 22% reduction in SERCA2 expression, a 23% increase in phospholamban (PLN) expression, and a 50% reduction in PLN phosphorylation in PVC-CM samples vs Sham. Computational analysis simulating a 20% decrease in SR-Ca2+ reuptake resulted in a ~ 22ms delay in Ca2+ signal decay, consistent with the experimental result described above. In conclusion, SERCA2 and PLB alterations described above have a modest contribution to functional adaptations observed in PVC-CM.

Abstract 10671: Similar Left Ventricular Remodeling Despite Different Coupling Intervals of Frequent Premature Ventricular Contractions

Introduction: Left ventricular (LV) post-extrasystolic potentiation (PESP) and dyssynchrony (LVD) are proposed mechanisms that may trigger premature ventricular contraction-induced cardiomyopathy (PVC-CM). While long-coupled (LC) PVCs are characterized by higher LVD and lower PESP, short-coupled (SC) PVCs have higher PESP and lower LVD. Methods: Twenty-four mongrel dogs implanted with right ventricular epicardial pacemakers were randomized to short-coupled (PVC-SC; 200 to 220-ms, n = 10), long-coupled (PVC-LC; 320 to 340-ms, n = 7) bigeminal PVCs, or no PVCs (sham; n = 7). Holter monitors were obtained to confirm PVC burdens. Echocardiograms were performed at baseline and regular intervals up to 12 weeks after assignment to assess for LV remodeling by investigators blinded to group assignments. Intra- and inter-group comparisons were performed at each time point. PVC-CM was defined as LV ejection fraction &lt; 50%. Results: Holter monitors confirmed similar PVC burdens in PVC-LC and PVC-SC groups. After 12 weeks (Table 1), PVC-CM developed in 9 (90%) PVC-SC and 5 (71%) PVC-LC animals (p = 0.5368) with similar LVEF reduction in both groups (PVC-SC: 44.4 ± 1.5%; PVC-LC: 44.7 ± 4.0%; p = 0.9953) compared to sham (62.6 ± 1.5%). LV end-diastolic volume was greater in the PVC-LC (67.5 ± 4.6 mL) compared to PVC-SC (57.5 ± 2.7 mL; p = 0.0171) and sham (52.1 ± 1.5 mL; p = 0.0004) groups. LV end-systolic volume and indices of LV mass were similarly elevated in PVC-SC and PVC-LC groups compared to sham. Conclusions: Short- and long-coupled PVCs did not differentially impact the incidence or severity of LV remodeling in this translational animal model of PVC-CM. This finding is compatible with preliminary clinical observations that PVC coupling interval does not predict the development of PVC-CM in humans. Our data suggest that PESP and LV dyssynchrony play equally important roles in the development of PVC-CM.

Post-extrasystolic potentiation differentiates “true” from “pseudo” Low-flow, Low-gradient aortic stenosis

Post-extrasystolic potentiation (PESP) is a marker of contractile reserve and refers to the augmentation of left ventricular contractility due to preload recruitment and rise in intracellular calcium following a premature beat. In this case report we show that PESP might be a safe and helpful aid to evaluate low flow, low gradient aortic stenosis and contractile reserve in the cathlab, thereby reducing the potential risk of complications associated with intravenous dobutamine evaluation and reducing unnecessary testing.

Post-extrasystolic potentiation as a predictor of premature ventricular contraction-cardiomyopathy in an animal model.

High premature ventricular contractions (PVCs) burden does not always predict the development of PVC-cardiomyopathy (CM). We sought to evaluate post-extrasystolic potentiation (PESP) of left ventricular ejection fraction (LVEF) to predict the severity of PVC-CM in an animal model. Right ventricular apical bigeminal PVCs were introduced for 12 weeks in 11 canines to induce PVC-CM. Echocardiograms were performed to obtain LVEF without ectopy (Echo-1) and during PVCs (200 and 350 ms coupling intervals, Echo-2, and Echo-3, respectively), and premature atrial contractions (PACs) (Echo-4) at baseline and after 12 weeks of bigeminal PVCs. PESP was calculated as delta-LVEF between the sinus beat post-ectopy LVEF (Echo-2, -3, and -4, respectively) and LVEF without PVC (Echo-1) at baseline and 12 weeks of high PVC burden. A hyperdynamic LV function (LVEF > 70%) was noted in all animals only with early-coupled PVCs (LVEF at 200 ms: 74.4 ± 6%) at baseline. While PVC PESP at 200 ms had a strong significant correlation with the final 12-week LVEF (R = 0.8, P = 0.003), PVC PESP at 350 ms and PAC PESP had a positive but non-significant correlation (R = 0.53, P = 0.09, and R = 0.29, P = 0.34, respectively). Premature ventricular contraction PESP at 350 ms was significantly higher after PVC-CM had developed (delta-LVEF baseline 2.7 ± 2.9% vs. 12 weeks 18.6 ± 12.3% P < 0.001). Bigeminal early-coupled PVCs cause hyperdynamic left ventricular function in the structurally normal canine heart due to PESP. The degree of PESP at baseline is inversely proportional to the PVC-CM severity at 12 weeks and maybe a predictor of PVC-CM as it may assess the myocardial adaptation reserve to PVCs.

Consequences of chronic frequent premature atrial contractions: Association with cardiac arrhythmias and cardiac structural changes.

Frequent premature ventricular contractions (PVCs) can cause cardiomyopathy (CM). Postextrasystolic potentiation (PESP) and irregularity have been in implicated as triggers of PVC-CM. Because both phenomena can also be found in premature atrial contractions (PACs), it is speculated that frequent PACs have similar consequences. A single-center, retrospective study included all consecutive patients undergoing a 14-day Holter monitors (November 2014 toOctober 2016). Patients were divided into four groups by ectopy burden group 1 (<1%) and remaining by tertiles (group 2-4). Echocardiographic and arrhythmic data were compared between PAC and PVC burdens. In addition, a translational PAC animal model was used to assess the chronic effects of frequent PACs. A total 846 patients were reviewed. In contrast to PVCs, we found no difference in left ventricular ejection fraction (LVEF), end-systolic and end-diastolic dimensions and presence of CM (LVEF <50%) between different PAC groups. Multivariate regression analysis demonstrated that only PVC burden predicted low EF (odds ratio, 1.1; confidence interval, 1.03-1.13; P = .001). While there was a weak correlation between PAC burden and supraventricular tachycardia (SVT) episodes and atrial fibrillation (AF) burden (r = 0.19; P < .001), there was no correlation between PAC burden and LVEF or CM. Finally, atrial bigeminy in our animal model did not significantly decrease LVEF after 3 months. PAC burden is associated with increased AF and SVT episodes. In contrast to a high PVC burden, a high PAC burden is not associated with CM. Our findings suggest that heart rate irregularity and/or PESP may play a minimal role in the pathophysiology of PVC-CM.

Safety of Continuous Postextrasystolic Pacing in the Human

Continuous postextrasystolic pacing is a potential positive inotropic treatment for several depressed myocardial states. The safety of this pacing, however, has been questioned since the mid‐1960's because the pacing markedly raises the myocardial oxygen consumption, thereby increasing the potential for proarrhythmia. To understand the actual safety of continuous postextrasystolic pacing, six clinical studies and case reports were reviewed involving a wide range of cardiovascular maladies (atrial or ventricular septal defect, congestive cardiomyopathy, heart failure, mitral or pulmonary stenosis, mitral, tricuspid, or aortic regurgitation, patent ductus arteriosis, mitral valve prolapse, coronary arterial‐arteriosclerotic heart disease, and pulmonary arterial hypertension): Braunwald E., et al. Amer. J. Med. 37: 700–711, 1964. Meijler, F. L. and D. Durrer. Bull. N. Y. Acad. Med. 41: 575–591, 1965. Lister, J. W., et al. Am. Heart J. 73: 362–368, 1967. Resnekov, L. Med. Clin. N. Amer. 54: 247–259, 1970. Gerschwind, H., et al. J. Am. Coll. Cardiol. 4: 216–225, 1984. Freudenberger, R., et al. J. Cardiac Fail. 14: 35–40, 2008. Patients received paired or coupled atrial, ventricular, or dual‐chamber pacing. Continuous postextrasystolic pacing in 63 of 63 patients resulted in zero incidences of ventricular tachyarrhythmia induction, including in 7 with a compromised coronary circulation. Only when a seventh clinical study was reviewed, involving myocardial infarction‐associated cardiogenic shock, did any arrhythmia occur, and only in 1 of 5 cases: Gourgon, R., et al. Paired Pulse Stimulation of the Heart. Proceedings of the Second Conference on Paired Pulse Stimulation and Postextrasystolic Potentiation in the Heart. 1968. pp. 36–51. Hence, when coronary arterial blood flow and myocardial oxygen supply are not compromised, and in the vast majority of cases where it is, continuous postextrasystolic potentiation pacing is a safe positive inotropic technique.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Hemodynamic consequences of premature ventricular contractions: Association of mechanical bradycardia and postextrasystolic potentiation with premature ventricular contraction-induced cardiomyopathy

The relationships between hemodynamic consequences of premature ventricular contractions (PVCs) and development of premature ventricular contraction-induced cardiomyopathy (PVC-CM) have not been investigated. The purpose of this study was to correlate concealed mechanical bradycardia and/or postextrasystolic potentiation (PEP) to PVC-CM. Invasive arterial pressure measurements from 17 patients with PVC-CM and 16 controls with frequent PVCs were retrospectively analyzed. PVCs were considered efficient (ejecting PVCs) when generating a measurable systolic arterial pressure. PEP was defined by a systolic arterial pressure of the post-PVC beat ≥5 mm Hg higher than the preceding sinus beat. Every PVC was analyzed for 10 minutes before ablation, and the electromechanical index (EMi = number of ejecting PVCs/total PVC) and postextrasystolic potentiation index (PEPi = number of PVCs with PEP/total PVC) were calculated. EMi was 29% ± 31% in PVC-CM and 78% ± 20% in controls (P <.0001). PEPi was 41% ± 28% in PVC-CM and 14% ± 10% in controls (P = .001). There was no control in groups of low EMi or high PEPi. EMi and PEPi were not significantly correlated to left ventricular dimensions or function in PVC-CM patients. PVC coupling interval was related to both ejecting PVCs and PEP. Patients with PVC-CM more often display nonejecting PVCs and PEP compared to controls.

An Augmented Negative Force-Frequency Relationship and Slowed Mechanical Restitution Are Associated With Increased Susceptibility to Drug-Induced Torsade de Pointes Arrhythmias in the Chronic Atrioventricular Block Dog.

Introduction: In the chronic AV-block (CAVB) dog model, structural, contractile, and electrical remodeling occur, which predispose the heart to dofetilide-induced Torsade de Pointes (TdP) arrhythmias. Previous studies found a relation between electrical remodeling and inducibility of TdP, while structural remodeling is not a prerequisite for arrhythmogenesis. In this study, we prospectively assessed the relation between in vivo markers of contractile remodeling and TdP inducibility.Methods: In 18 anesthetized dogs, the maximal first derivative of left ventricular pressure (LV dP/dtmax) was assessed at acute AV-block (AAVB) and after 2 weeks of chronic AV-block (CAVB2). Using pacing protocols, three markers of contractile remodeling, i.e., force-frequency relationship (FFR), mechanical restitution (MR), and post-extrasystolic potentiation (PESP) were determined. Infusion of dofetilide (0.025 mg/kg in 5 min) was used to test for TdP inducibility.Results: After infusion of dofetilide, 1/18 dogs and 12/18 were susceptible to TdP-arrhythmias at AAVB and CAVB2, respectively (p = 0.001). The inducible dogs at CAVB2 showed augmented contractility at a CL of 1200 ms (2354 ± 168 mmHg/s in inducible dogs versus 1091 ± 59 mmHg/s in non-inducible dogs, p < 0.001) with a negative FFR, while the non-inducible dogs retained their positive FFR. The time constant (TC) of the MR curve was significantly higher in the inducible dogs (158 ± 7 ms versus 97 ± 8 ms, p < 0.0001). Furthermore, a linear correlation was found between a weighted score of the number and severity of arrhythmias and contractile parameters, i.e., contractility at CL of 1200 ms (r = 0.73, p = 0.002), the slope of the FFR (r = -0.58, p = 0.01) and the TC of MR (r = 0.66, p = 0.003). Thus, more severe arrhythmias were seen in dogs with the most pronounced contractile remodeling.Conclusion: Contractile remodeling is concomitantly observed with susceptibility to dofetilide-induced TdP-arrhythmias. The inducible dogs show augmented contractile remodeling compared to non-inducible dogs, as seen by a negative FFR, higher maximal response of MR and PESP and slowed MR kinetics. These altered contractility parameters could reflect disrupted Ca2+ handling and Ca2+-overload, which predispose the heart to delayed- and early afterdepolarizations that could trigger TdP-arrhythmias.

Influence of Amiodarone and Dronedarone on the Force-Interval Dependence of Rat Myocardium.

The antiarrhythmic effect of amiodarone and its analogue dronedarone is caused by their direct actions on several cardiomyocyte sarcolemmal ion currents. However, whether their effects are related to intracellular calcium levels is not exactly known. Ca2+ cycling refers to the release and reuptake of intracellular Ca2+, which induces muscle contraction and relaxation and determines the force-interval dependence. This study aimed to evaluate the influence of amiodarone and dronedarone on the force-interval relationship. Materials and Results. The work was performed on the papillary muscles of the left ventricle of male Wistar rats. Muscle perfusion was performed at 36.5°C with oxygenated Krebs-Henseleit solution with baseline stimulation 0.5 Hz. The postrest test (4-60 s) and the extrasystolic exposure (0.2-1.5 s) were evaluated. Inotropic reaction to the test exposure was evaluated before and after muscle perfusion with solution containing amiodarone (10−6 M) or dronedarone (10−6 M) during 10 min. Amiodarone or dronedarone led to decrease of the amplitude of extrasystolic contractions of the papillary muscles. The amplitude of postextrasystolic contractions after short extrasystolic intervals on the background of the drugs was increased. Amiodarone and dronedarone led to increase of the amplitude of postrest contractions. Conclusions. Dronedarone reduces the excitability of cardiomyocyte sarcolemma to a greater extent than amiodarone. Amiodarone and dronedarone are able to increase postextrasystolic and postrest potentiation. The effect of amiodarone on postextrasystolic and postrest potentiation is more pronounced in comparison with dronedarone.

Reduced Arrhythmogenic Potential of Ventricular Paired Pacing During Myocardial Infarction

Since the 1960's, the clinical use of ventricular paired pacing (VPP), a form of continuous postextrasystolic potentiation, to augment cardiac function in cardiogenic shock has been prevented by the stigma of ventricular arrhythmogenesis. Historically, this perception was based on very limited human data on the sickest of the sick when many current medical treatments were long into the future. One such treatment is the use of β‐adrenergic receptor blockade, well accepted now, but antithetical then. A meta‐analysis of canine studies of myocardial infarction was performed to understand the effect β‐blockade had on the incidence of ventricular fibrillation during the VPP treatment

Post-Extrasystolic Potentiation asaPredictor of Recovery of LeftVentricularDysfunction After Radiofrequency Catheter Ablation.

This study hypothesizes that post-extrasystolic potentiation reflects left ventricle contractile reserve and therefore may predict an improvement of premature ventricular contraction (PVC)-induced cardiomyopathy after PVC ablation. Post-extrasystolic potentiation is a physiologic phenomenon of blood pressure accentuation after a PVC beat. We performed a retrospective study of patients with a PVC burden of≥10% PVC/24 h and left ventricular ejection fraction (LVEF) of<50% who underwent successful ablation between January 1, 2009, to June 30, 2015. Subjects were classified as having reversible (a final LVEF≥50%) or irreversible (final LVEF<50%) LV dysfunction on a follow-up echocardiogram. A reference (control) group with≥10% PVC but normal LV function was also identified. Sixty-one patients (age 68 ± 11 years, 98% male) were studied: 30 with preserved and 31 with reduced LVEF. During median follow-up of 9.4 months, the LVEF of 17 of 31 reduced EF patients improved (reversible) but 14 did not (irreversible). The post-PVC beat systolic blood pressure (SBP) (mmHg) increase ranged from 12.1 in control subjects (LVEF >50%) to 11.5 in reversible patients to 5 in irreversible patients. In multivariate analysis, the independent predictors of reversible LV function were post-PVC SBP rise (odds ratio [OR]: 4.61; 95% confidence interval [CI]: 1.45 to 15.83 per 5-mm Hg increase; p< 0.001), post-PVC pulse pressure change (OR: 5.2; 95% CI: 2.3 to 18.6 per 5-mm Hg increase; p< 0.001), and PVC QRS duration (OR: 2.78; 95% CI: 1.63 to 10.94 per 10-ms increase; p< 0.001). In patients with LV dysfunction and frequent PVC, post-PVC SBP accentuation may be a marker forsubsequent recovery of LVEF after ablation in presumed PVC-induced cardiomyopathy.

Absence of post-extrasystolic potentiation in takotsubo cardiomyopathy: Another piece of the puzzle?

BackgroundTakotsubo cardiomyopathy (TCM) is an intriguing phenomenon characterized by transient and reversible left ventricular (LV) dysfunction despite angiographically unobstructed coronary arteries. The detailed pathophysiology of stunned, viable myocardium in TCM remains to be determined. Post-extrasystolic potentiation (PESP), the phenomenon of enhanced LV contractility following extrasystole, has been used to assess myocardial viability. MethodsUtilizing a local database, we identified 74 cases that met the modified Mayo Clinic criteria for TCM between October 2004 and March 2016. The patients undergoing left ventriculography were assessed for the presence of fortuitously provoked extrasystoles and the presence or absence of PESP. ResultsThe baseline characteristics of TCM were 93.2% female patients with median age of 69 and majority cases were apical type (77%). In-hospital mortality was observed in 3 cases (4.1%), all of which were apical type. We observed improved ejection fraction after extrasystole compared to baseline, however stunned myocardium had minimal PESP whereas unaffected myocardium showed marked potentiation. ConclusionExtrasystoles in TCM failed to elicit PESP in affected LV segments despite viability in those segments, in turn implicating a calcium handling abnormality in TCM. Potential explanations of our results may be that catecholamine excess caused maximum calcium release so that an extrasystole could not enhance contractility any further, or that there is a regional insensitivity to calcium release due to a disturbance of the calcium regulatory system at the molecular level despite the bolus of calcium availability provided by the extrasystole.

Regular pulse rate but irregular heart rate?

The 12-lead ECG shows a ventricular bigeminy with right bundle branch block, which is evidence of a left ventricular origin. The inferior axis and repetitive monomorphic occurrence points to an origin from the outflow tract. Thus, the diagnosis is repetitive left ventricular outflow tract premature beats. This extrasystole can be found in healthy individuals and does not increase the risk of sudden cardiac death. However, due to the short coupling interval of the extrasystole there is almost no diastolic filling before the extrasystolic beat, thus leading to a pulse deficit which is aggravated by the lack of a subsequent sinus beat (postextrasystolic pause). The subsequent sinus beat is augmented due to postextrasystolic potentiation and a prolonged diastole. During bigeminy there is a 2:1 pulse deficit leading to the reported slow but regular pulse rates of the patient. Outflow tract premature beats often show a fixed coupling interval due to triggered activity during phase III of the action potential (early afterdepolarisation) and thus sometimes responds to calcium channel inhibitors such as verapamil. Beta-blockers may be effective but sides effects such as arterial hypotension decrease compliance, especially in young adults. Accordingly, in this patient, ablation of the arrhythmia was scheduled. For electrophysiological mapping, a deflectable mapping and ablation catheter was introduced retrogradely into the left ventricle and mapping of the earliest ventricular activity was performed during spontaneous ventricular premature beats. In this case, earliest activity was recorded above the aortic valve inside the left coronary sinus cusp. Pacing from this site revealed a similar 12-lead ECG morphology as during spontaneous ventricular premature beats. Due to the proximity to the left main coronary artery, a left coronary angiography catheter was positioned into the left main coronary artery (Fig. 1 and 2) and simultaneous visualisation during ablation at this site was performed to identify impeding damage to the coronary vessel [1]. Ablation was performed using an irrigated catheter and the arrhythmia terminated after 10 seconds of radiofrequency ablation (Fig. 3). On the right side of the ECG you can see ST elevation which is documented near the coronary artery. After the ablation, this completely resolved. Since then, the patient has been free of symptoms and repetitive Holter ECGs did not show a recurrence of the arrhythmia. Fig. 1 Ablation catheter in the ascending aorta below the left main coronary artery as visualised by a diagnostic angiography catheter (JL-4). Additional electrode catheters are positioned in the high right atrium and right ventricle. Due to the anatomical ... Fig. 2 Under such ablations at critical points, imaging from different levels is important to safely prevent injury to the coronary arteries. (LAD left anterior descending) Fig. 3 12-lead ECG with termination of the premature beats (arrow) under radiofrequency ablation. On the right side of the ECG you can see ST elevation (*) which is documented near the coronary artery. After the ablation, these completely resolved

Regular pulse rate but irregular heart rate?

The 12-lead ECG shows a ventricular bigeminy with right bundle branch block, which is evidence of a left ventricular origin. The inferior axis and repetitive monomorphic occurrence points to an origin from the outflow tract. Thus, the diagnosis is repetitive left ventricular outflow tract premature beats. This extrasystole can be found in healthy individuals and does not increase the risk of sudden cardiac death. However, due to the short coupling interval of the extrasystole there is almost no diastolic filling before the extrasystolic beat, thus leading to a pulse deficit which is aggravated by the lack of a subsequent sinus beat (postextrasystolic pause). The subsequent sinus beat is augmented due to postextrasystolic potentiation and a prolonged diastole. During bigeminy there is a 2:1 pulse deficit leading to the reported slow but regular pulse rates of the patient. Outflow tract premature beats often show a fixed coupling interval due to triggered activity during phase III of the action potential (early afterdepolarisation) and thus sometimes responds to calcium channel inhibitors such as verapamil. Beta-blockers may be effective but sides effects such as arterial hypotension decrease compliance, especially in young adults. Accordingly, in this patient, ablation of the arrhythmia was scheduled. For electrophysiological mapping, a deflectable mapping and ablation catheter was introduced retrogradely into the left ventricle and mapping of the earliest ventricular activity was performed during spontaneous ventricular premature beats. In this case, earliest activity was recorded above the aortic valve inside the left coronary sinus cusp. Pacing from this site revealed a similar 12-lead ECG morphology as during spontaneous ventricular premature beats. Due to the proximity to the left main coronary artery, a left coronary angiography catheter was positioned into the left main coronary artery (Fig. 1 and 2) and simultaneous visualisation during ablation at this site was performed to identify impeding damage to the coronary vessel [1]. Ablation was performed using an irrigated catheter and the arrhythmia terminated after 10 seconds of radiofrequency ablation (Fig. 3). On the right side of the ECG you can see ST elevation which is documented near the coronary artery. After the ablation, this completely resolved. Since then, the patient has been free of symptoms and repetitive Holter ECGs did not show a recurrence of the arrhythmia. Fig. 1 Ablation catheter in the ascending aorta below the left main coronary artery as visualised by a diagnostic angiography catheter (JL-4). Additional electrode catheters are positioned in the high right atrium and right ventricle. Due to the anatomical ... Fig. 2 Under such ablations at critical points, imaging from different levels is important to safely prevent injury to the coronary arteries. (LAD left anterior descending) Fig. 3 12-lead ECG with termination of the premature beats (arrow) under radiofrequency ablation. On the right side of the ECG you can see ST elevation (*) which is documented near the coronary artery. After the ablation, these completely resolved

Post-extrasystolic Blood Pressure Potentiation as a Risk Predictor in Cardiac Patients

For more than 100 years physicians have observed that heartbeats following extrasystolic beats are characterised by augmented myocardial contractility. This phenomenon was termed post-extrasystolic potentiation (PESP). In the 1970s it was first noted that PESP measured at the blood pressure level is typically pronounced in heart failure patients. Only recently, it was shown that PESP measured non-invasively as post-extrasystolic blood pressure potentiation was a strong and independent predictor of death in survivors of myocardial infarction and in patients with chronic heart failure. A similar parameter (PESPAfib) can be also assessed in patients with atrial fibrillation. PESP and PESPAfib can be understood as non-invasive parameters that indicate myocardial dysfunction. They have the potential to improve risk stratification strategies for cardiac patients.

Post-extrasystolic Potentiation: Link between Ca(2+) Homeostasis and Heart Failure?

Post-extrasystolic potentiation (PESP) describes the phenomenon of increased contractility of the beat following an extrasystole and has been attributed to changes in Ca(2+) homeostasis. While this effect has long been regarded to be a normal physiological phenomenon, a number of reports describe an enhanced potentiation of the post-extrasystolic beat in heart failure patients. The exact mechanism of this increased PESP is unknown, but disruption of normal Ca(2+) handling in heart failure may be the underlying cause. The use of PESP as a prognostic marker or therapeutic intervention have recently regained new attention, however, the value of the application of PESP in the clinic is still under debate. In this review, the mechanism of PESP with regard to Ca(2+) in the normal and failing heart will be discussed and the possible diagnostic and therapeutic role of this phenomenon will be explored.