Post-COVID-19 Condition.

An estimated 10-15% of those infected with SARS-CoV-2 may have post-COVID-19 condition. Common lingering signs and symptoms include shortness of breath, fatigue, high heart rate, and memory and cognitive dysfunction even several months after infection, often impacting survivors' quality of life. The prevalence and duration of individual symptoms remain difficult to ascertain due to the lack of standardized research methods across various studies and limited patient follow-up in clinical studies. Nonetheless, data indicate post-COVID-19 condition may occur independent of acuity of initial infection, hospitalization status, age, or pre-existing comorbidities. Risk factors may include female sex and underlying respiratory or psychiatric disease. Supportive therapies to mitigate symptoms remain the mainstay of treatment. Reassuringly, most patients experience a reduction in symptoms by 1 year. The use of a universal case definition and shared research methods will allow for further clarity regarding the pervasiveness of this entity and its long-term health consequences.

Catheter ablation of typical atrial flutter improves cardiac chamber size and function.

INTRODUCTION: Cavo-tricuspid isthmus (CTI) dependent atrial flutter (AFL) is one of the most common atrial arrhythmias involving the right atrium (RA) for which radiofrequency catheter ablation has been widely used as a therapy of choice. However, there is limited data on the effect of this intervention on cardiac size and function. METHODS: A retrospective study was conducted on 468 patients who underwent ablation for CTI dependent typical AFL at a single institution between 2010 and 2019. After excluding patients with congenital or rheumatic heart disease, heart transplant recipients, or those without baseline echocardiogram, a total of 130 patients were included in the analysis. Echocardiographic data were analyzed at baseline before ablation, and at early follow-up within 1-year postablation. Follow-up echocardiographic data was available for 55 patients. RESULTS: Of the 55 patients with CTI-AFL, the mean age was 64.2 ± 14.8 years old with 14.5% (n = 8) female. The average left ventricular ejection fraction (LVEF) significantly improved on follow-up echo (40.2 ± 16.9 to 50.4 ± 14.9%, p < .0001), of which 50% of patients had an improvement in LVEF of at least 10%. There was a significant reduction in left atrial volume index (82.74 ± 28.5 to 72.96 ± 28 mL/m2 , p = .008) and RA volume index (70.62 ± 25.6 to 64.15 ± 31 mL/m2 , p = .046), and a significant improvement in left atrial reservoir strain (13.04 ± 6.8 to 19.10 ± 7.7, p < .0001). CONCLUSIONS: Patients who underwent CTI dependent AFL ablation showed an improvement in cardiac size and function at follow-up evaluation. While long-term results are still unknown, these findings indicate that restoration of sinus rhythm in patients with typical AFL is associated with improvement in atrial size and left ventricular function.

Automated prediction of isthmus areas in scar-related atrial tachycardias using artificial intelligence.

INTRODUCTION: Ablation of scar-related reentrant atrial tachycardia (SRRAT) involves identification and ablation of a critical isthmus. A graph convolutional network (GCN) is a machine learning structure that is well-suited to analyze the irregularly-structured data obtained in mapping procedures and may be used to identify potential isthmuses. METHODS: Electroanatomic maps from 29 SRRATs were collected, and custom electrogram features assessing key tissue and wavefront properties were calculated for each point. Isthmuses were labeled off-line. Training data was used to determine the optimal GCN parameters and train the final model. Putative isthmus points were predicted in the training and test populations and grouped into proposed isthmus areas based on density and distance thresholds. The primary outcome was the distance between the centroids of the true and closest proposed isthmus areas. RESULTS: A total of 193 821 points were collected. Thirty isthmuses were detected in 29 tachycardias among 25 patients (median age 65.0, 5 women). The median (IQR) distance between true and the closest proposed isthmus area centroids was 8.2 (3.5, 14.4) mm in the training and 7.3 (2.8, 16.1) mm in the test group. The mean overlap in areas, measured by the Dice coefficient, was 11.5 ± 3.2% in the training group and 13.9 ± 4.6% in the test group. CONCLUSION: A GCN can be trained to identify isthmus areas in SRRATs and may help identify critical ablation targets.

2024 European Heart Rhythm Association/Heart Rhythm Society/Asia Pacific Heart Rhythm Society/Latin American Heart Rhythm Society expert consensus statement on catheter and surgical ablation of atrial fibrillation.

In the last three decades, ablation of atrial fibrillation (AF) has become an evidence-based safe and efficacious treatment for managing the most common cardiac arrhythmia. In 2007, the first joint expert consensus document was issued, guiding healthcare professionals involved in catheter or surgical AF ablation. Mounting research evidence and technological advances have resulted in a rapidly changing landscape in the field of catheter and surgical AF ablation, thus stressing the need for regularly updated versions of this partnership which were issued in 2012 and 2017. Seven years after the last consensus, an updated document was considered necessary to define a contemporary framework for selection and management of patients considered for or undergoing catheter or surgical AF ablation. This consensus is a joint effort from collaborating cardiac electrophysiology societies, namely the European Heart Rhythm Association, the Heart Rhythm Society, the Asia Pacific Heart Rhythm Society, and the Latin American Heart Rhythm Society .

Long-term complications of COVID-19.

SARS-CoV-2 has rapidly spread across the globe and infected hundreds of millions of people worldwide. As our experience with this virus continues to grow, our understanding of both short-term and long-term complications of infection with SARS-CoV-2 continues to grow as well. Just as there is heterogeneity in the acute infectious phase, there is heterogeneity in the long-term complications seen following COVID-19 illness. The purpose of this review article is to present the current literature with regards to the epidemiology, pathophysiology, and proposed management algorithms for the various long-term sequelae that have been observed in each organ system following infection with SARS-CoV-2. We will also consider future directions, with regards to newer variants of the virus and their potential impact on the long-term complications observed.

Evolution of tricuspid valve regurgitation after implantation of a leadless pacemaker: A single center experience, systematic review, and meta-analysis.

INTRODUCTION: Conventional transvenous pacemaker leads may interfere with the tricuspid valve leaflets, tendinous chords, and papillary muscles, resulting in significant tricuspid valve regurgitation (TR). Leadless pacemakers (LLPMs) theoretically cause less mechanical interference with the tricuspid valve apparatus. However, data on TR after LLPM implantation are sparse and conflicting. Our goal was to investigate the prevalence of significant TR before and after LLPM implantation. METHODS: Patients who received a leadless LLPM (Micra™ TPS, Medtronic) between May 2016 and May 2021 at our center were included in this observational study if they had at least a pre- and postinterventional echocardiogram (TTE). The evolution of TR severity was assessed. Following a systematic literature review on TR evolution after implantation of a LLPM, data were pooled in a random-effects meta-analysis. RESULTS: We included 69 patients (median age 78 years [interquartile range (IQR) 72-84 years], 26% women). Follow-up duration between baseline and follow-up TTE was 11.4 months (IQR 3.5-20.1 months). At follow-up, overall TR severity was not different compared to baseline (p = .49). Six patients (9%) had new significant TR during follow-up after LLPM implantation, whereas TR severity improved in seven patients (10%). In the systematic review, we identified seven additional articles that investigated the prevalence of significant TR after LLPM implantation. The meta-analysis based on 297 patients failed to show a difference in significant TR before and after LLPM implantation (risk ratio 1.22, 95% confidence interval 0.97-1.53, p = .11). CONCLUSION: To date, there is no substantial evidence for a significant change in TR after implantation of a LLPM.

Critical appraisal of technologies to assess electrical activity during atrial fibrillation: a position paper from the European Heart Rhythm Association and European Society of Cardiology Working Group on eCardiology in collaboration with the Heart Rhythm Society, Asia Pacific Heart Rhythm Society, Latin American Heart Rhythm Society and Computing in Cardiology.

We aim to provide a critical appraisal of basic concepts underlying signal recording and processing technologies applied for (i) atrial fibrillation (AF) mapping to unravel AF mechanisms and/or identifying target sites for AF therapy and (ii) AF detection, to optimize usage of technologies, stimulate research aimed at closing knowledge gaps, and developing ideal AF recording and processing technologies. Recording and processing techniques for assessment of electrical activity during AF essential for diagnosis and guiding ablative therapy including body surface electrocardiograms (ECG) and endo- or epicardial electrograms (EGM) are evaluated. Discussion of (i) differences in uni-, bi-, and multi-polar (omnipolar/Laplacian) recording modes, (ii) impact of recording technologies on EGM morphology, (iii) global or local mapping using various types of EGM involving signal processing techniques including isochronal-, voltage- fractionation-, dipole density-, and rotor mapping, enabling derivation of parameters like atrial rate, entropy, conduction velocity/direction, (iv) value of epicardial and optical mapping, (v) AF detection by cardiac implantable electronic devices containing various detection algorithms applicable to stored EGMs, (vi) contribution of machine learning (ML) to further improvement of signals processing technologies. Recording and processing of EGM (or ECG) are the cornerstones of (body surface) mapping of AF. Currently available AF recording and processing technologies are mainly restricted to specific applications or have technological limitations. Improvements in AF mapping by obtaining highest fidelity source signals (e.g. catheter-electrode combinations) for signal processing (e.g. filtering, digitization, and noise elimination) is of utmost importance. Novel acquisition instruments (multi-polar catheters combined with improved physical modelling and ML techniques) will enable enhanced and automated interpretation of EGM recordings in the near future.

Guidance for Cardiac Electrophysiology During the COVID-19 Pandemic from the Heart Rhythm Society COVID-19 Task Force; Electrophysiology Section of the American College of Cardiology; and the Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology, American Heart Association.

Coronavirus disease 2019 (COVID-19) is a global pandemic that is wreaking havoc on the health and economy of much of human civilization. Electrophysiologists have been impacted personally and professionally by this global catastrophe. In this joint article from representatives of the Heart Rhythm Society, the American College of Cardiology, and the American Heart Association, we identify the potential risks of exposure to patients, allied healthcare staff, industry representatives, and hospital administrators. We also describe the impact of COVID-19 on cardiac arrhythmias and methods of triage based on acuity and patient comorbidities. We provide guidance for managing invasive and noninvasive electrophysiology procedures, clinic visits, and cardiac device interrogations. In addition, we discuss resource conservation and the role of telemedicine in remote patient care along with management strategies for affected patients.

Clinical and cardiac characteristics of COVID-19 mortalities in a diverse New York City Cohort.

INTRODUCTION: Electrocardiographic characteristics in COVID-19-related mortality have not yet been reported, particularly in racial/ethnic minorities. METHODS AND RESULTS: We reviewed demographics, laboratory and cardiac tests, medications, and cardiac rhythm proximate to death or initiation of comfort care for patients hospitalized with a positive SARS-CoV-2 reverse-transcriptase polymerase chain reaction in three New York City hospitals between March 1 and April 3, 2020 who died. We described clinical characteristics and compared factors contributing toward arrhythmic versus nonarrhythmic death. Of 1258 patients screened, 133 died and were enrolled. Of these, 55.6% (74/133) were male, 69.9% (93/133) were racial/ethnic minorities, and 88.0% (117/133) had cardiovascular disease. The last cardiac rhythm recorded was VT or fibrillation in 5.3% (7/133), pulseless electrical activity in 7.5% (10/133), unspecified bradycardia in 0.8% (1/133), and asystole in 26.3% (35/133). Most 74.4% (99/133) died receiving comfort measures only. The most common abnormalities on admission electrocardiogram included abnormal QRS axis (25.8%), atrial fibrillation/flutter (14.3%), atrial ectopy (12.0%), and right bundle branch block (11.9%). During hospitalization, an additional 17.6% developed atrial ectopy, 14.7% ventricular ectopy, 10.1% atrial fibrillation/flutter, and 7.8% a right ventricular abnormality. Arrhythmic death was confirmed or suspected in 8.3% (11/133) associated with age, coronary artery disease, asthma, vasopressor use, longer admission corrected QT interval, and left bundle branch block (LBBB). CONCLUSIONS: Conduction, rhythm, and electrocardiographic abnormalities were common during COVID-19-related hospitalization. Arrhythmic death was associated with age, coronary artery disease, asthma, longer admission corrected QT interval, LBBB, ventricular ectopy, and usage of vasopressors. Most died receiving comfort measures.

Performance of electrophysiology procedures at an academic medical center amidst the 2020 coronavirus (COVID-19) pandemic.

A global coronavirus (COVID-19) pandemic occurred at the start of 2020 and is already responsible for more than 74 000 deaths worldwide, just over 100 years after the influenza pandemic of 1918. At the center of the crisis is the highly infectious and deadly SARS-CoV-2, which has altered everything from individual daily lives to the global economy and our collective consciousness. Aside from the pulmonary manifestations of disease, there are likely to be several electrophysiologic (EP) sequelae of COVID-19 infection and its treatment, due to consequences of myocarditis and the use of QT-prolonging drugs. Most crucially, the surge in COVID-19 positive patients that have already overwhelmed the New York City hospital system requires conservation of hospital resources including personal protective equipment (PPE), reassignment of personnel, and reorganization of institutions, including the EP laboratory. In this proposal, we detail the specific protocol changes that our EP department has adopted during the COVID-19 pandemic, including performance of only urgent/emergent procedures, after hours/7-day per week laboratory operation, single attending-only cases to preserve PPE, appropriate use of PPE, telemedicine and video chat follow-up appointments, and daily conferences to collectively manage the clinical and ethical dilemmas to come. We discuss also discuss how we perform EP procedures on presumed COVID positive and COVID tested positive patients to highlight issues that others in the EP community may soon face in their own institution as the virus continues to spread nationally and internationally.

Management of Arrhythmias Associated with COVID-19.

PURPOSE OF REVIEW: Cardiac arrhythmias are known complications in patients with COVID-19 infection that may persist even after recovery from infection. A review of the spectrum of cardiac arrhythmias due to COVID-19 infection and current guidelines and assessment or risk and benefit of management considerations is necessary as the population of patients infected and covering from COVID-19 continues to grow. RECENT FINDINGS: Cardiac arrhythmias such as atrial fibrillation, supraventricular tachycardia, complete heart block, and ventricular tachycardia occur in patients infected, recovering and recovered from COVID-19. Personalized care while balancing risk/benefit of medical or invasive therapy is necessary to improve care of patients with arrhythmias. Providers must provide thorough follow-up care and use necessary precaution while caring for COVID-19 patients.

Cardiac electrophysiology consultative experience at the epicenter of the COVID-19 pandemic in the United States.

BACKGROUND: The COVID-19 pandemic has greatly altered the practice of cardiac electrophysiology around the world for the foreseeable future. Professional organizations have provided guidance for practitioners, but real-world examples of the consults and responsibilities cardiac electrophysiologists face during a surge of COVID-19 patients is lacking. METHODS: In this observational case series we report on 29 consecutive inpatient electrophysiology consultations at a major academic medical center in New York City, the epicenter of the pandemic in the United States, during a 2 week period from March 30-April 12, 2020, when 80% of hospital beds were occupied by COVID-19 patients, and the New York City metropolitan area accounted for 10% of COVID-19 cases worldwide. RESULTS: Reasons for consultation included: Atrial tachyarrhythmia (31%), cardiac implantable electronic device management (28%), bradycardia (14%), QTc prolongation (10%), ventricular arrhythmia (7%), post-transcatheter aortic valve replacement conduction abnormality (3.5%), ventricular pre-excitation (3.5%), and paroxysmal supraventricular tachycardia (3.5%). Twenty-four patients (86%) were positive for COVID-19 by nasopharyngeal swab. All elective procedures were canceled, and only one urgent device implantation was performed. Thirteen patients (45%) required in-person evaluation and the remainder were managed remotely. CONCLUSION: Our experience shows that the application of a massive alteration in workflow and personnel forced by the pandemic allowed our team to efficiently address the intersection of COVID-19 with a range of electrophysiology issues. This experience will prove useful as guidance for emerging hot spots or areas affected by future waves of the pandemic.

Leadless pacemaker implantation: A feasible and reasonable option in transcatheter heart valve replacement patients.

BACKGROUND: Leadless pacemakers (LPMs) have been shown to have lower postoperative complications than traditional permanent pacemakers but there have been no studies on the outcomes of LPMs in patients with transcatheter heart valve replacements (THVRs). This study determined outcomes of LPMs compared to transvenous single-chamber pacemakers (SCPs) post-THVR. METHODS: This is a retrospective single-center study including 10 patients who received LPMs post-THVR between February 2017 and August 2018 and a comparison group of 23 patients who received SCP post-THVR between July 2008 and August 2018. LPM or SCP was implanted at the discretion of electrophysiologists for atrial fibrillation with slow ventricular response or sinus node dysfunction with need for single-chamber pacing only. RESULTS: LPMs were associated with decreased tricuspid regurgitation (P = 0.04) and decreased blood loss during implantation (7.5 ± 2.5 cc for LPMs vs 16.8 ± 3.2 cc for SCPs, P = 0.03). Five LPM patients had devices positioned in the right ventricular septum as seen on transthoracic echocardiogram. Frequency of ventricular pacing was similar between LPM and SCP groups. In the LPM group, one case was complicated by a pseudoaneurysm and one death was due to noncardiac causes. There was one pneumothorax and one pocket infection in the SCP group. CONCLUSIONS: In this small retrospective study, LPMs were feasible post-THVR and found to perform as well as SCPs, had less intraprocedural blood loss, and were associated with less tricuspid regurgitation. Further, larger studies are required to follow longer-term outcomes and complications.

Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models.

Anti-angiogenic therapies have shown limited efficacy in the clinical management of metastatic disease, including lung metastases. Moreover, the mechanisms via which tumours resist anti-angiogenic therapies are poorly understood. Importantly, rather than utilizing angiogenesis, some metastases may instead incorporate pre-existing vessels from surrounding tissue (vessel co-option). As anti-angiogenic therapies were designed to target only new blood vessel growth, vessel co-option has been proposed as a mechanism that could drive resistance to anti-angiogenic therapy. However, vessel co-option has not been extensively studied in lung metastases, and its potential to mediate resistance to anti-angiogenic therapy in lung metastases is not established. Here, we examined the mechanism of tumour vascularization in 164 human lung metastasis specimens (composed of breast, colorectal and renal cancer lung metastasis cases). We identified four distinct histopathological growth patterns (HGPs) of lung metastasis (alveolar, interstitial, perivascular cuffing, and pushing), each of which vascularized via a different mechanism. In the alveolar HGP, cancer cells invaded the alveolar air spaces, facilitating the co-option of alveolar capillaries. In the interstitial HGP, cancer cells invaded the alveolar walls to co-opt alveolar capillaries. In the perivascular cuffing HGP, cancer cells grew by co-opting larger vessels of the lung. Only in the pushing HGP did the tumours vascularize by angiogenesis. Importantly, vessel co-option occurred with high frequency, being present in >80% of the cases examined. Moreover, we provide evidence that vessel co-option mediates resistance to the anti-angiogenic drug sunitinib in preclinical lung metastasis models. Assuming that our interpretation of the data is correct, we conclude that vessel co-option in lung metastases occurs through at least three distinct mechanisms, that vessel co-option occurs frequently in lung metastases, and that vessel co-option could mediate resistance to anti-angiogenic therapy in lung metastases. Novel therapies designed to target both angiogenesis and vessel co-option are therefore warranted. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

The PDZ motif of the α1C subunit is not required for surface trafficking and adrenergic modulation of CaV1.2 channel in the heart.

Voltage-gated Ca(2+) channels play a key role in initiating muscle excitation-contraction coupling, neurotransmitter release, gene expression, and hormone secretion. The association of CaV1.2 with a supramolecular complex impacts trafficking, localization, turnover, and, most importantly, multifaceted regulation of its function in the heart. Several studies hint at an important role for the C terminus of the α1C subunit as a hub for multidimensional regulation of CaV1.2 channel trafficking and function. Recent studies have demonstrated an important role for the four-residue PDZ binding motif at the C terminus of α1C in interacting with scaffold proteins containing PDZ domains, in the subcellular localization of CaV1.2 in neurons, and in the efficient signaling to cAMP-response element-binding protein in neurons. However, the role of the α1C PDZ ligand domain in the heart is not known. To determine whether the α1C PDZ motif is critical for CaV1.2 trafficking and function in cardiomyocytes, we generated transgenic mice with inducible expression of an N-terminal FLAG epitope-tagged dihydropyridine-resistant α1C with the PDZ motif deleted (ΔPDZ). These mice were crossed with α-myosin heavy chain reverse transcriptional transactivator transgenic mice, and the double-transgenic mice were fed doxycycline. The ΔPDZ channels expressed, trafficked to the membrane, and supported robust excitation-contraction coupling in the presence of nisoldipine, a dihydropyridine Ca(2+) channel blocker, providing functional evidence that they appropriately target to dyads. The ΔPDZ Ca(2+) channels were appropriately regulated by isoproterenol and forskolin. These data indicate that the α1C PDZ motif is not required for surface trafficking, localization to the dyad, or adrenergic stimulation of CaV1.2 in adult cardiomyocytes.

Mechanism of tumour vascularization in experimental lung metastases.

The appearance of lung metastases is associated with poor outcome and the management of patients with secondary pulmonary tumours remains a clinical challenge. We examined the vascularization process of lung metastasis in six different preclinical models and found that the tumours incorporated the pre-existing alveolar capillaries (ie vessel co-option). During the initial phase of vessel co-option, the incorporated capillaries were still sheathed by pneumocytes, but these incorporated vessels subsequently underwent different fates dependent on the model. In five of the models examined (B16, HT1080, HT25, C26, and MAT B-III), the tumour cells gradually stripped the pneumocytes from the vessels. These dissected pneumocytes underwent fragmentation, but the incorporated microvessels survived. In the sixth model (C38), the tumour cells failed to invade the alveolar walls. Instead, they induced the development of vascularized desmoplastic tissue columns. Finally, we examined the process of arterialization in lung metastases and found that they became arterialized when their diameter grew to exceed 5 mm. In conclusion, our data show that lung metastases can vascularize by co-opting the pulmonary microvasculature. This is likely to have important clinical implications, especially with respect to anti-angiogenic therapies.

Atrial Tachycardias After Atrial Fibrillation Ablation Manifest Different Waveform Characteristics: Implications for Characterizing Tachycardias.

INTRODUCTION: Atrial fibrillation (AF) ablation patients often manifest atrial tachycardias (AT) with atypical ECG morphologies that preclude accurate localization and mechanism. Diagnostic maneuvers used to define ATs during electrophysiology studies can be limited by tachycardia termination or transformation. Additional methods of characterizing post-AF ablation ATs are required. METHODS AND RESULTS: We evaluated the utility of noninvasive ECG signal analytics in postablation AF patients for the following features: (1) Localization of ATs (i.e., right vs. left atrium), and (2) Identification of common left AT mechanisms (i.e., focal vs. macroreentrant). Atrial waveforms from the surface ECG were used to analyze (1) spectral organization, including dominant amplitude (DA) and mean spectral profile (MP), and (2) temporospatial variability, using temporospatial correlation coefficients. We studied 94 ATs in 71 patients who had undergone prior pulmonary vein isolation for AF and returned for a second ablation: (1) right atrial cavotricuspid-isthmus dependent (CTI) ATs (n = 21); (2) left atrial macroreentrant ATs (n = 41) and focal ATs (n = 32). Right CTI ATs manifested higher DAs and lower MPs than left ATs, indicative of greater stability and less complexity in the frequency spectrum. Left macroreentrant ATs possessed higher temporospatial organization than left focal ATs. CONCLUSIONS: Noninvasively recorded atrial waveform signal analyses show that right ATs possess more stable activation properties than left ATs, and left macroreentrant ATs manifest higher temporospatial organization than left focal ATs. Further prospective analyses evaluating the role these novel ECG-derived tools can play to help localize and identify mechanisms of common ATs in AF ablation patients are warranted.

Enhanced efferocytosis of apoptotic cardiomyocytes through myeloid-epithelial-reproductive tyrosine kinase links acute inflammation resolution to cardiac repair after infarction.

RATIONALE: Efficient clearance of apoptotic cells (efferocytosis) is a prerequisite for inflammation resolution and tissue repair. After myocardial infarction, phagocytes are recruited to the heart and promote clearance of dying cardiomyocytes. The molecular mechanisms of efferocytosis of cardiomyocytes and in the myocardium are unknown. The injured heart provides a unique model to examine relationships between efferocytosis and subsequent inflammation resolution, tissue remodeling, and organ function. OBJECTIVE: We set out to identify mechanisms of dying cardiomyocyte engulfment by phagocytes and, for the first time, to assess the causal significance of disrupting efferocytosis during myocardial infarction. METHODS AND RESULTS: In contrast to other apoptotic cell receptors, macrophage myeloid-epithelial-reproductive tyrosine kinase was necessary and sufficient for efferocytosis of cardiomyocytes ex vivo. In mice, Mertk was specifically induced in Ly6c(LO) myocardial phagocytes after experimental coronary occlusion. Mertk deficiency led to an accumulation of apoptotic cardiomyocytes, independently of changes in noncardiomyocytes, and a reduced index of in vivo efferocytosis. Importantly, suppressed efferocytosis preceded increases in myocardial infarct size and led to delayed inflammation resolution and reduced systolic performance. Reduced cardiac function was reproduced in chimeric mice deficient in bone marrow Mertk; reciprocal transplantation of Mertk(+/+) marrow into Mertk(-/-) mice corrected systolic dysfunction. Interestingly, an inactivated form of myeloid-epithelial-reproductive tyrosine kinase, known as solMER, was identified in infarcted myocardium, implicating a natural mechanism of myeloid-epithelial-reproductive tyrosine kinase inactivation after myocardial infarction. CONCLUSIONS: These data collectively and directly link efferocytosis to wound healing in the heart and identify Mertk as a significant link between acute inflammation resolution and organ function.

Reduced vascular smooth muscle BK channel current underlies heart failure-induced vasoconstriction in mice.

Excessively increased peripheral vasoconstriction is a hallmark of heart failure (HF). Here, we show that in mice with systolic HF post-myocardial infarction, the myogenic tone of third-order mesenteric resistance vessels is increased, the vascular smooth muscle (VSM) membrane potential is depolarized by ~20 mV, and vessel wall intracellular [Ca(2+)] is elevated relative to that in sham-operated control mice. Despite the increased [Ca(2+)], the frequency and amplitude of spontaneous transient outward currents (STOCs), mediated by large conductance, Ca(2+)-activated BK channels, were reduced by nearly 80% (P<0.01) and 25% (P<0.05), respectively, in HF. The expression of the BK α and ß1 subunits was reduced in HF mice compared to controls (65 and 82% lower, respectively, P<0.01). Consistent with the importance of a reduction in BK channel expression and function in mediating the HF-induced increase in myogenic tone are two further findings: a blunting of paxilline-induced increase in myogenic tone in HF mice compared to controls (0.9 vs. 10.9%, respectively), and that HF does not alter the increased myogenic tone of BK ß1-null mice. These findings identify electrical dysregulation within VSM, specifically the reduction of BK currents, as a key molecular mechanism sensitizing resistance vessels to pressure-induced vasoconstriction in systolic HF.