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BackgroundInappropriate sinus tachycardia (IST) is defined as resting heart rate >100 beats/min and average 24-hour heart rate >90 beats/min. It is associated with distressing symptoms and significant loss of quality of life. Drugs are not effective in symptom control of IST in up to 30% of patients. Catheter ablation of the sinus node has a high recurrence rate, and the complications are significant. Recently, a novel hybrid sinus node-sparing ablation approach for IST was described.ObjectiveThe objective of the Hybrid Epicardial and Endocardial Sinus Node Sparing Ablation Therapy for Inappropriate Sinus Tachycardia (HEAL-IST) investigational device exemption trial (NCT05280093) is to evaluate safety and effectiveness of the hybrid sinus node-sparing ablation procedure for the treatment of symptomatic, drug-refractory or drug-intolerant IST.MethodsThe HEAL-IST trial is a prospective, multicenter, pivotal, single-arm trial. Up to 142 subjects in up to 40 centers will be treated in the trial with a Bayesian adaptive design.ResultsSubjects will be assessed for primary safety through 30 days post-hybrid ablation procedure. The primary effectiveness endpoint will be freedom from IST at 12 months. Freedom from IST will be defined as mean heart rate of ≤90 beats/min or at least a 15% reduction in mean heart rate as compared with baseline, in the absence of new or higher dosage of previously failed medications at a 24-month follow-up assessment.ConclusionThe HEAL-IST trial is the first multicenter trial evaluating hybrid IST ablation in patients with symptomatic IST and refractory or intolerant to drugs. The results of this study will help guide decision making regarding the best management in this population.

Heart failure (HF) remains a global public health burden and often results following myocardial infarction (MI). Following injury, cardiac fibrosis forms in the myocardium which greatly hinders cellular function, survival, and recruitment, thus severely limits tissue regeneration. Here, we leverage biophysical microstructural cues made of hyaluronic acid (HA) loaded with the anti-fibrotic proteoglycan decorin to more robustly attenuate cardiac fibrosis after acute myocardial injury. Microrods showed decorin incorporation throughout the entirety of the hydrogel structures and exhibited first-order release kinetics in vitro. Intramyocardial injections of saline (n = 5), microrods (n = 7), decorin microrods (n = 10), and free decorin (n = 4) were performed in male rat models of ischemia-reperfusion MI to evaluate therapeutic effects on cardiac remodeling and function. Echocardiographic analysis demonstrated that rats treated with decorin microrods (5.21% ± 4.29%) exhibited significantly increased change in ejection fraction (EF) at 8 weeks post-MI compared to rats treated with saline (-4.18% ± 2.78%, p

Recent data suggest that epicardial left atrial appendage closure (LAAC) is associated with several short-term neurohormonal effects. However, the long-term effects are currently unknown. To investigate the effects of percutaneous epicardial left atial appendage (LAA) exclusion using LARIAT on neurohormonal profiles at long-term follow-up. In a prospective single centre study, 60 patients with long-standing, persistent atrial fibrillation (AF) LARIAT were treated. The major hormones of the adrenergic system, renin-angiotensin-aldosterone system (RAAS), and natriuretic peptides were assessed before the intervention and at regular intervals during the following two years. In patients with epicardial LAAC, atrial natriuretic peptide (ANP) levels were significantly increased from baseline at 24 h and decreased at 7 days, 1 month, and 3 months, while remaining unchanged at 12 and 24 months. Noradrenaline levels were significantly lower at 24 h, 7 days, 1 month, 6 months, 12 months, and 24 months, while epinephrine levels decreased significantly at 1 month, 6 months, 12 months, and 24 months. Plasma renin activity significantly decreased at 7 days, 1 month, 6 months, 12 months, and 24 months, while aldosterone levels significantly decreased at 6 months, 12 months, and 24 months. Endothelin-1 and vasopressin showed a significant increase and decrease, respectively, at 24 h, 7 days, 1 month, 6 months, 12 months, and 24 months. There was also a significant decrease in systolic and diastolic blood pressure at 3 months, 6 months, 1 year, and 2 years after the intervention. Epicardial LAAC in AF patients is associated with persistent neurohormonal changes favouring blood pressure reduction.

ObjectivesThis study sought to identify acute changes in human atrial electrophysiology during alcohol exposure.BackgroundThe mechanism by which a discrete episode of atrial fibrillation (AF) occurs remains unknown. Alcohol appears to increase the risk for AF, providing an opportunity to study electrophysiologic effects that may render the heart prone to arrhythmia.MethodsIn this randomized, double-blinded, placebo-controlled trial, intravenous alcohol titrated to 0.08% blood alcohol concentration was compared with a volume and osmolarity-matched, masked, placebo in patients undergoing AF ablation procedures. Right, left, and pulmonary vein atrial effective refractory periods (AERPs) and conduction times were measured pre- and post-infusion. Isoproterenol infusions and burst atrial pacing were used to assess AF inducibility.ResultsOf 100 participants (50 in each group), placebo recipients were more likely to be diabetic (22% vs. 4%; p = 0.007) and to have undergone a prior AF ablation (36% vs. 22%; p = 0.005). Pulmonary vein AERPs decreased an average of 12 ms (95% confidence interval: 1 to 22 ms; p = 0.026) in the alcohol group, with no change in the placebo group (p = 0.98). Whereas no statistically significant differences in continuously assessed AERPs were observed, the proportion of AERP sites tested that decreased with alcohol (median: 0.5; interquartile range: 0.6 to 0.6) was larger than with placebo (median: 0.4; interquartile range: 0.2 to 0.6; p = 0.0043). No statistically significant differences in conduction times or in the proportion with inducible AF were observed.ConclusionsAcute exposure to alcohol reduces AERP, particularly in the pulmonary veins. These data demonstrate a direct mechanistic link between alcohol, a common lifestyle exposure, and immediate proarrhythmic effects in human atria. (How Alcohol Induces Atrial Tachyarrhythmias Study [HOLIDAY]; NCT01996943).

Atrial fibrillation (AF) is a cardiac rhythm disorder associated with increased morbidity and mortality. It is the leading risk factor for cardioembolic stroke and its early detection is crucial in both primary and secondary stroke prevention. Continuous monitoring of cardiac rhythm is today possible thanks to consumer-grade wearable devices, enabling transformative diagnostic and patient management tools. Such monitoring is possible using low-cost easy-to-implement optical sensors that today equip the majority of wearables. These sensors record blood volume variations-a technology known as photoplethysmography (PPG)-from which the heart rate and other physiological parameters can be extracted to inform about user activity, fitness, sleep, and health. Recently, new wearable devices were introduced as being capable of AF detection, evidenced by large prospective trials in some cases. Such devices would allow for early screening of AF and initiation of therapy to prevent stroke. This review is a summary of a body of work on AF detection using PPG. A thorough account of the signal processing, machine learning, and deep learning approaches used in these studies is presented, followed by a discussion of their limitations and challenges towards clinical applications.

We report the case of a 60-year-old patient who underwent orthotopic heart transplant 14 years earlier. Routine echocardiography showed giant masses in the left atrium. There were no symptoms or thromboembolic events in the past. Magnetic resonance imaging study revealed very enlarged left atrium (8.7 × 10.6 cm) occupied by irregular smooth mass (7 × 5 × 6.1 cm) with a stalk that was attached to the posterior left atrial wall in the area of graft suture lines. Intraoperative examination revealed a massive thrombus (12 × 10 cm) that filled almost the entire left atrial area.

Ischemic heart disease represents the leading cause of death worldwide. Heart failure following myocardial infarction (MI) is associated with severe fibrosis formation and cardiac remodeling. Recently, injectable hydrogels have emerged as a promising approach to repair the infarcted heart and improve heart function through minimally invasive administration. Here, a novel injectable human amniotic membrane (hAM) matrix is developed to enhance cardiac regeneration following MI. Human amniotic membrane is isolated from human placenta and engineered to be a thermoresponsive, injectable gel around body temperature. Ultrasound-guided injection of hAM matrix into rat MI hearts significantly improves cardiac contractility, as measured by ejection fraction (EF), and decrease fibrosis. The results of this study demonstrate the feasibility of engineering as an injectable hAM matrix and its efficacy in attenuating degenerative changes in cardiac function following MI, which may have broad applications in tissue regeneration.

IntroductionThe prevalence of heart failure increases in the aging population and following myocardial infarction (MI), yet the extracellular matrix (ECM) remodeling underpinning the development of aging- and MI-associated cardiac fibrosis remains poorly understood. A link between inflammation and fibrosis in the heart has long been appreciated, but has mechanistically remained undefined. We investigated the expression of a novel protein, extracellular matrix protein 1 (ECM1) in the aging and infarcted heart.MethodsYoung adult (3-month old) and aging (18-month old) C57BL/6 mice were assessed. Young mice were subjected to left anterior descending artery-ligation to induce MI, or transverse aortic constriction (TAC) surgery to induce pressure-overload cardiomyopathy. Left ventricle (LV) tissue was collected early and late post-MI/TAC. Bone marrow cells (BMCs) were isolated from young healthy mice, and subject to flow cytometry. Human cardiac fibroblast (CFb), myocyte, and coronary artery endothelial & smooth muscle cell lines were cultured; human CFbs were treated with recombinant ECM1. Primary mouse CFbs were cultured and treated with recombinant angiotensin-II or TGF-β1. Immunoblotting, qPCR and mRNA fluorescent in-situ hybridization (mRNA-FISH) were conducted on LV tissue and cells.ResultsECM1 expression was upregulated in the aging LV, and in the infarct zone of the LV early post-MI. No significant differences in ECM1 expression were found late post-MI or at any time-point post-TAC. ECM1 was not expressed in any resident cardiac cells, but ECM1 was highly expressed in BMCs, with high ECM1 expression in granulocytes. Flow cytometry of bone marrow revealed ECM1 expression in large granular leucocytes. mRNA-FISH revealed that ECM1 was indeed expressed by inflammatory cells in the infarct zone at day-3 post-MI. ECM1 stimulation of CFbs induced ERK1/2 and AKT activation and collagen-I expression, suggesting a pro-fibrotic role.ConclusionsECM1 expression is increased in ageing and infarcted hearts but is not expressed by resident cardiac cells. Instead it is expressed by bone marrow-derived granulocytes. ECM1 is sufficient to induce cardiac fibroblast stimulation in vitro. Our findings suggest ECM1 is released from infiltrating inflammatory cells, which leads to cardiac fibroblast stimulation and fibrosis in aging and MI. ECM1 may be a novel intermediary between inflammation and fibrosis.

Repairing cardiac tissue after myocardial infarction (MI) is one of the most challenging goals in tissue engineering. Following ischemic injury, significant matrix remodeling and the formation of avascular scar tissue significantly impairs cell engraftment and survival in the damaged myocardium. This limits the efficacy of cell replacement therapies, demanding strategies that reduce pathological scarring to create a suitable microenvironment for healthy tissue regeneration. Here, we demonstrate the successful fabrication of discrete hyaluronic acid (HA)-based microrods to provide local biochemical and biomechanical signals to reprogram cells and attenuate cardiac fibrosis. HA microrods were produced in a range of physiological stiffness and shown to degrade in the presence of hyaluronidase. Additionally, we show that fibroblasts interact with these microrods in vitro, leading to significant changes in proliferation, collagen expression and other markers of a myofibroblast phenotype. When injected into the myocardium of an adult rat MI model, HA microrods prevented left ventricular wall thinning and improved cardiac function at 6 weeks post infarct.

Two patients with long-standing atrial fibrillation (AF) refractory to medical management and with prior pulmonary vein isolation underwent a new hybrid epicardial/endocardial subxyphoid approach for AF ablation and left atrial appendage (LAA) ligation. Pulmonary vein and LA posterior wall isolation, as well as LAA exclusion were achieved in both patients. There were no procedural complications. Both patients remain in sinus rhythm. Both patients are off antiarrhythmic medications.

INTRODUCTION:Left atrial appendage closure (LAAC) with LARIAT offers an alternative to oral anticoagulation (OAC) for patients with atrial fibrillation. The aim of this study was to present long-term clinical outcomes of LAAC in these patients (AF). MATERIAL AND METHODS:A prospective, single-center study was performed in 139 patients undergoing LAAC with Lariat. Thromboembolic events, severe bleeding and mortality rate were recorded. The reduction in risk of thromboembolism and bleeding after LAAC was calculated. RESULTS:The mean CHADS2-score was 1.8 ± 1.0, mean CHA2DS2-VASc score was 2.9 ± 1.6 and HAS-BLED score was 3.1 ± 1.1. After 428.4 patient-years of follow-up (mean 4.2±1.0 years), the thromboembolism rate was 0.6% with a calculated thromboembolism risk reduction of 81%. The severe bleeding rate was 0.8%; calculated bleeding risk reduction was 78%. The overall mortality rate was 1.6%. CONCLUSIONS:Long-term outcomes show that LAAC with Lariat is a safe and effective treatment for stroke prevention and bleeding risk reduction in AF patients with a high level of underlying risk.

When challenged by hemodynamic stress, aging hearts respond differently to young hearts. Preclinical models of heart disease should take into account the effects of age. However, in the transverse aortic constriction (TAC) model of pressure-overload cardiomyopathy, the larger aorta of aging mice has not previously been taken into account. First, we studied the aortic size in mice, and found that the aortic cross-sectional area (CSA) is 28% larger in aging mice than in young adult mice (P=0.001). We then performed TAC to make the same proportional reduction in CSA in young and aging mice. This produced the same pressure gradient across the constriction and the same rise in B-type natriuretic peptide expression. Young mice showed acute deterioration in systolic function assessed by pressure-volume loops, progressive LV remodeling on echocardiography, and a 50% mortality at 12 weeks post-TAC. In contrast, aging mice showed no acute deterioration in systolic function, much less ventricular remodeling and were protected from death. Aging mice also showed significantly increased levels of matrix metalloproteinase-3 (MMP-3; 3.2 fold increase, P

BackgroundAtrial refractoriness may be an important determinant of atrial fibrillation (AF) risk, but its measurement is not clinically accessible. Because the QT interval predicts incident AF and the atrium and ventricle share repolarizing ion currents, we investigated the association between an individual's QT interval and atrial effective refractory period (AERP).MethodsIn paroxysmal AF patients presenting for catheter ablation, the QT interval was measured from the surface 12-lead electrocardiogram. The AERP was defined as the longest S1-S2 coupling interval without atrial capture using a 600-ms drive cycle length.ResultsIn 28 patients, there was a positive correlation between QTc and mean AERP. After multivariate adjustment, a 1-ms increase in QTc predicted a 0.70-ms increase in AERP.ConclusionsThe QTc interval reflects the AERP, suggesting that the QTc interval may be used as a marker of atrial refractoriness relevant to assessing AF risk and mechanism-specific therapeutic strategies.

BackgroundLeft atrial appendage (LAA) exclusion has been performed in patients with atrial fibrillation (AF) to prevent thrombus formation and subsequent cardioembolic events. Left atrial electrical remodeling is a recognized factor in the recurrence of AF. The effects of LAA exclusion on P-wave characteristics and left atrial electrical remodeling have not been well described. The purpose of this study was to evaluate the effect of LAA ligation on P-wave morphology in patients with AF.Methods and resultsFifteen patients who were in sinus rhythm during the LAA ligation procedure were included in the study. We evaluated the P-wave characteristics, including P-wave duration, P-wave amplitude, PQ interval, and P-wave dispersion, before and after ligation. Eleven patients had paroxysmal AF and 4 patients had persistent AF (12 male patients and 3 female patients). P-wave duration immediately after ligation was significantly shorter compared with baseline in all limb leads except lead aVR (P

Chronic fibrosis caused by acute myocardial infarction (MI) leads to increased morbidity and mortality due to cardiac dysfunction. We have developed a therapeutic materials strategy that aims to mitigate myocardial fibrosis by utilizing injectable polymeric microstructures to mechanically alter the microenvironment. Polymeric microstructures were fabricated using photolithographic techniques and studied in a three-dimensional culture model of the fibrotic environment and by direct injection into the infarct zone of adult rats. Here, we show dose-dependent down-regulation of expression of genes associated with the mechanical fibrotic response in the presence of microstructures. Injection of this microstructured material into the infarct zone decreased levels of collagen and TGF-β, increased elastin deposition and vascularization in the infarcted region, and improved functional outcomes after six weeks. Our results demonstrate the efficacy of these discrete anti-fibrotic microstructures and suggest a potential therapeutic materials approach for combatting pathologic fibrosis.

BackgroundThe arrhythmic role of the left atrial appendage (LAA) has been implicated in the maintenance of persistent atrial fibrillation. LAA isolation with catheter ablation has been successful but is limited by the risk of tamponade and electromechanical dissociation with the potential for LAA thrombus formation.ObjectiveTo assess whether LAA ligation results in LAA electrical isolation.MethodsA total of 68 patients with contraindication or intolerance to oral anticoagulation therapy underwent LAA ligation with the LARIAT suture delivery device. Patients had unipolar [n = 30(44%)] or bipolar [n = 38(56%)] voltage measurements pre- and post-LAA ligation.ResultsAll 68 patients underwent successful LAA ligation. There was a statistically significant reduction in the mean LAA voltage from pre-ligation (unipolar pre-ligation voltage 1.1 ± 0.53 mV; bipolar pre-ligation voltage 4.7 ± 2.83 mV) to post-ligation (unipolar post-ligation voltage 0.3 ± 0.38 mV; bipolar post-ligation voltage 0.6 ± 0.27 mV). Ninety-four percent of the patients had a reduction in the LAA voltage after the closure of the snare, with 10 of 30 (33%) of the patients having complete elimination of LAA voltage with the initial tightening of the suture. Pacing from the LAA after the closure of the snare resulted in lack of capture of the left atrium in 28 of 31 patients.ConclusionsThe snare closure of the LAA using the LARIAT device produces an acute reduction in the LAA voltage and inhibits the capture of the left atrium during LAA pacing. Future studies are needed to determine whether LAA ligation affects atrial fibrillation burden.

BackgroundAging is associated with higher incidence of heart failure and death following myocardial infarction (MI). The molecular and cellular changes that lead to these worse outcomes are not known.Methods and resultsYoung and aging mice underwent induction of MI by LAD ligation. There was a significant increase in mortality in the aging mice. Neither the young nor aging hearts after MI had inducible ventricular tachycardia. Cardiomyocyte apoptosis increases early after MI in young and aging mice, but to a much greater degree in the aging mice. Caspase inhibition with Ac-DEVD-CHO resulted in a 61% reduction in activated caspase-3 and an 84% reduction in apoptosis in cardiomyocytes in young mice (P

BackgroundLeft ventricular (LV) wall stress reduction is a cornerstone in treating heart failure. Large animal models and computer simulations indicate that adding non-contractile material to the damaged LV wall can potentially reduce myofiber stress. We sought to quantify the effects of a novel implantable hydrogel (Algisyl-LVR™) treatment in combination with coronary artery bypass grafting (i.e. Algisyl-LVR™+CABG) on both LV function and wall stress in heart failure patients.Methods and resultsMagnetic resonance images obtained before treatment (n=3), and at 3 months (n=3) and 6 months (n=2) afterwards were used to reconstruct the LV geometry. Cardiac function was quantified using end-diastolic volume (EDV), end-systolic volume (ESV), regional wall thickness, sphericity index and regional myofiber stress computed using validated mathematical modeling. The LV became more ellipsoidal after treatment, and both EDV and ESV decreased substantially 3 months after treatment in all patients; EDV decreased from 264 ± 91 ml to 146 ± 86 ml and ESV decreased from 184 ± 85 ml to 86 ± 76 ml. Ejection fraction increased from 32 ± 8% to 47 ± 18% during that period. Volumetric-averaged wall thickness increased in all patients, from 1.06 ± 0.21 cm (baseline) to 1.3 ± 0.26 cm (3 months). These changes were accompanied by about a 35% decrease in myofiber stress at end-of-diastole and at end-of-systole. Post-treatment myofiber stress became more uniform in the LV.ConclusionsThese results support the novel concept that Algisyl-LVR™+CABG treatment leads to decreased myofiber stress, restored LV geometry and improved function.

ObjectivesThe study tested the hypothesis that augmentation of the left ventricular (LV) wall thickness with direct intramyocardial injections of alginate hydrogel implants (AHI) reduces LV cavity size, restores LV shape, and improves LV function in dogs with heart failure (HF).BackgroundProgressive LV dysfunction, enlargement, and chamber sphericity are features of HF associated with increased mortality and morbidity.MethodsStudies were performed in 14 dogs with HF produced by intracoronary microembolizations (LV ejection fraction [EF]

Unlike some organs, the heart is unable to repair itself after injury. Human embryonic stem cells (hESCs) grow and divide indefinitely while maintaining the potential to develop into many tissues of the body. As such, they provide an unprecedented opportunity to treat human diseases characterized by tissue loss. We have identified early myocardial precursors derived from hESCs (hMPs) using an α-myosin heavy chain (αMHC)-GFP reporter line. We have demonstrated by immunocytochemistry and quantitative real-time PCR (qPCR) that reporter activation is restricted to hESC-derived cardiomyocytes (CMs) differentiated in vitro, and that hMPs give rise exclusively to muscle in an in vivo teratoma formation assay. We also demonstrate that the reporter does not interfere with hESC genomic stability. Importantly, we show that hMPs give rise to atrial, ventricular and specialized conduction CM subtypes by qPCR and microelectrode array analysis. Expression profiling of hMPs over the course of differentiation implicate Wnt and transforming growth factor-β signaling pathways in CM development. The identification of hMPs using this αMHC-GFP reporter line will provide important insight into the pathways regulating human myocardial development, and may provide a novel therapeutic reagent for the treatment of cardiac disease.

BackgroundThe extracellular matrix plays an important role in tissue regeneration. We investigated whether extracellular matrix protein fragments could be targeted with antibodies to ischemically injured myocardium to promote angiogenesis and myocardial repair.Methodology/principal findingsFour peptides, 2 derived from fibronectin and 2 derived from Type IV Collagen, were assessed for in vitro and in vivo tendencies for angiogenesis. Three of the four peptides--Hep I, Hep III, RGD--were identified and shown to increase endothelial cell attachment, proliferation, migration and cell activation in vitro. By chemically conjugating these peptides to an anti-myosin heavy chain antibody, the peptides could be administered intravenously and specifically targeted to the site of the myocardial infarction. When administered into Sprague-Dawley rats that underwent ischemia-reperfusion myocardial infarction, these peptides produced statistically significantly higher levels of angiogenesis and arteriogenesis 6 weeks post treatment.Conclusions/significanceWe demonstrated that antibody-targeted ECM-derived peptides alone can be used to sufficiently alter the extracellular matrix microenvironment to induce a dramatic angiogenic response in the myocardial infarct area. Our results indicate a potentially new non-invasive strategy for repairing damaged tissue, as well as a novel tool for investigating in vivo cell biology.

Pleiotrophin (PTN) is a growth factor with both pro-angiogenic and limited pro-tumorigenic activity. We evaluated the potential for PTN to be used for safe angiogenic gene therapy using the full length gene and a truncated gene variant lacking the domain implicated in tumorigenesis. Mouse myoblasts were transduced to express full length or truncated PTN (PTN or T-PTN), along with a LacZ reporter gene, and injected into mouse limb muscle and myocardium. In cultured myoblasts, PTN was expressed and secreted via the Golgi apparatus, but T-PTN was not properly secreted. Nonetheless, no evidence of uncontrolled growth was observed in cells expressing either form of PTN. PTN gene delivery to myocardium, and non-ischemic skeletal muscle, did not result in a detectable change in vascularity or function. In ischemic hindlimb at 14 days post-implantation, intramuscular injection with PTN-expressing myoblasts led to a significant increase in skin perfusion and muscle arteriole density. We conclude that (1) delivery of the full length PTN gene to muscle can be accomplished without tumorigenesis, (2) the truncated PTN gene may be difficult to use in a gene therapy context due to inefficient secretion, (3) PTN gene delivery leads to functional benefit in the mouse acute ischemic hindlimb model. [ABSTRACT FROM AUTHOR]