Clinical Characteristics and Outcomes in Patients With Atrial Fibrillation and Pathogenic TTN Variants.

BACKGROUND: TTN encodes a sarcomeric protein called titin. Pathogenic rare variants in TTN are the most common finding in patients with atrial fibrillation (AF) and positive genetic testing. OBJECTIVES: This study sought to define the characteristics and outcomes in patients with AF and pathogenic TTN variants compared with genotype-negative patients with AF. METHODS: Patients who presented initially with AF were enrolled in an AF registry. Retrospectively they underwent research sequencing for cardiomyopathy and arrhythmia genes. TTN(+) AF cases were defined as participants with pathogenic or likely pathogenic (P/LP) rare variants located in exons with high cardiac expression. They were matched 1:2 with control subjects with no P/LP variants. Phenotyping used retrospective manual chart review. RESULTS: Among 2794 participants; 57 (2.0%) TTN(+) AF cases were identified and matched with 114 control subjects. Low QRS complex voltage was present more often in TTN(+) AF cases (18% vs 5%; P < 0.01), with no difference in PR, QRS interval, or QTc. More TTN(+) AF cases had persistent AF at enrollment (44% vs 30%; P = 0.028) and had undergone multiple cardioversions (61% vs. 37%; P < 0.01). By end of follow-up (median 8.3 years; Q1, Q3: 4.5, 13.7 years), 11% of TTN(+) AF cases developed sustained ventricular tachycardia/ventricular fibrillation, 44% left ventricular (LV) systolic dysfunction (LV ejection fraction <50%), and 47% met a combined endpoint of sustained ventricular tachycardia/ventricular fibrillation or LV systolic dysfunction. CONCLUSIONS: TTN(+) AF patients undergo more cardioversions and have more persistent forms of AF. Approximately 50% develop LV systolic dysfunction and/or malignant ventricular arrhythmias. These results highlight the need for diagnostic evaluation and management in TTN(+) patients beyond the usual care for AF.

Ablation for Atrial Fibrillation in Patients With Rare Pathogenic Variants in Cardiomyopathy and Arrhythmia Genes.

BACKGROUND: Patients with rare, pathogenic cardiomyopathy (CM) and arrhythmia variants can present with atrial fibrillation (AF). The efficacy of AF ablation in these patients is unknown. OBJECTIVE: This study tested the hypotheses that: 1) patients with a pathogenic variant in any CM or arrhythmia gene have increased recurrence following AF ablation; and 2) patients with a pathogenic variant associated with a specific gene group (arrhythmogenic left ventricular CM [ALVC], arrhythmogenic right ventricular CM, dilated CM, hypertrophic CM, or a channelopathy) have increased recurrence. METHODS: We performed a prospective, observational, cohort study of patients who underwent AF catheter ablation and whole exome sequencing. The primary outcome measure was ≥30 seconds of any atrial tachyarrhythmia that occurred after a 90-day blanking period. RESULTS: Among 1,366 participants, 109 (8.0%) had a pathogenic or likely pathogenic (P/LP) variant in a CM or arrhythmia gene. In multivariable analysis, the presence of a P/LP variant in any gene was not significantly associated with recurrence (HR 1.15; 95% CI 0.84-1.60; P = 0.53). P/LP variants in the ALVC gene group, predominantly LMNA, were associated with increased recurrence (n = 10; HR 3.75; 95% CI 1.84-7.63; P < 0.001), compared with those in the arrhythmogenic right ventricular CM, dilated CM, hypertrophic CM, and channelopathy gene groups. Participants with P/LP TTN variants (n = 46) had no difference in recurrence compared with genotype-negative-controls (HR 0.93; 95% CI 0.54-1.59; P = 0.78). CONCLUSIONS: Our results support the use of AF ablation for most patients with rare pathogenic CM or arrhythmia variants, including TTN. However, patients with ALVC variants, such as LMNA, may be at a significantly higher risk for arrhythmia recurrence.

Termination Without Global Propagation in Re-Entrant Ventricular Tachycardia: Electrophysiologic Characteristics and 3D-Electroanatomical Mapping Analysis.

BACKGROUND: Termination of ventricular tachycardia (VT) by a pacing stimulus that does not generate a QRS complex (termination without global propagation [TWGP]) can be a marker for a critical re-entry circuit isthmus. However, the electrophysiologic and anatomic features of these sites and their relation to VT substrate defined by 3-dimensional electroanatomical maps (3D-EAM) remain unknown. OBJECTIVES: This retrospective study aimed to characterize TWGP sites and their relation to VT substrate identified by 3D-EAM. METHODS: A total of 632 consecutive cases of catheter ablation for scar-related VT at 2 University medical centers were reviewed to identify TWGP. RESULTS: TWGP was observed 12 times at 11 different sites in 10 patients (5 ischemic cardiomyopathy). The TWGP stimulus fell immediately before or synchronous with the QRS in all cases, and evidence of local capture despite absence of a QRS complex was observed 6 times. In 5 sites, pacing after VT termination produced a QRS different than the VT. Four sites were in dense scar areas (<0.1 mV), and 6 in abnormal low voltage zone (0.1-1.5 mV). Additional mapping or ablation that abolished VT were consistent with the TWGP site being in a VT isthmus. A substrate marker for VT of late potentials, evoked delayed potentials, or slow conduction was present at 6 of 11 TWGP sites. CONCLUSIONS: TWGP may be a marker for detecting a re-entry circuit isthmus that has escaped detection based on electrogram or pace mapping-based substrate mapping.

Mapping Extracellular Protein-Protein Interactions Using Extracellular Proximity Labeling (ePL).

Proximity labeling (PL) has given researchers the tools to explore protein-protein interactions (PPIs) in living systems; however, most PL studies are performed on intracellular targets. We have adapted the original PL method to investigate PPIs within the extracellular compartment, which we term extracellular PL (ePL). To demonstrate the utility of this modified technique, we investigated the interactome of the matrisome protein TIMP2. TIMPs are a family of multifunctional proteins that were initially defined by their ability to inhibit metalloproteinases, the major mediators of extracellular matrix (ECM) turnover. TIMP2 exhibits broad expression and is often abundant in both normal and diseased tissues. Understanding the functional transformation of matrisome regulators, such as TIMP2, during disease progression is essential for the development of ECM-targeted therapeutics. Using dual orientation fusion proteins of TIMP2 with BioID2/TurboID, we describe the TIMP2 proximal interactome (MassIVE MSV000095637). We also illustrate how the TIMP2 interactome changes in the presence of different stimuli, in different cell types, in unique culture conditions (2D vs 3D), and with different reaction kinetics, demonstrating the power of this technique versus classical PPI methods. We propose that screening of matrisome targets in disease models using ePL will reveal new therapeutic targets for further comprehensive studies.

Substrate Characterization and Outcomes of Ventricular Tachycardia Ablation in Amyloid Cardiomyopathy: A Multicenter Study.

BACKGROUND: Sustained ventricular tachycardia (VT) in cardiac amyloidosis is uncommon, and the substrate and outcomes of catheter ablation are not defined. METHODS: We included 22 consecutive patients (mean age, 68±10 years; male sex, 91%) with cardiac amyloidosis (ATTR [transthyretin], n=16; light chain, n=6) undergoing catheter ablation for VT/ventricular fibrillation (VF) between 2013 and 2023 in a retrospective, observational, international study. The primary efficacy outcome was recurrent VT/VF during follow-up, while the primary safety end point included major procedure-related adverse events. RESULTS: The indication for ablation was drug-refractory VT in 17 patients (77%), and premature ventricular complex-initiated polymorphic VT/VF in 5 patients (23%). Catheter ablation was performed using endocardial (n=17.77%) or endo-epicardial approaches (n=5.23%). Complete endocardial electroanatomical voltage maps of the left and right ventricles were obtained in 17 (77%) and 10 (45%) patients, respectively. Each patient had evidence of low-voltage areas, most commonly involving the interventricular septum (n=16); late potentials were recorded in 16 patients (73%). A median of 1 (1-2) VT was inducible per patient; 12 of the 26 mappable VTs (46%) originated from the interventricular septum. Complete procedural success was achieved in 16 patients (73%), with 4 (18%) major procedure-related adverse events. After a median follow-up of 32 (14-42) months, sustained VT/VF recurrence was observed in 9 patients (41%); survival free from VT/VF recurrence was 56% (95% CI, 36%-86%) at 36-month follow-up, and most patients remained on antiarrhythmic drugs. A significant reduction in per patient implantable cardioverter defibrillator therapies was noted in the 6-month period after ablation (before: 6 [4-9] versus after: 0 [0-0]; P<0.001). In multivariable analysis, complete procedural success was associated with reduced risk of recurrent VT/VF (hazard ratio, 0.002; P=0.034). CONCLUSIONS: Catheter ablation can achieve control of recurrent VT/VF in more than half of patients with cardiac amyloidosis, and the reduction in VT/VF burden post-ablation may be relevant for quality of life. Septal substrate and risk of procedure-related complications challenge successful management of patients with cardiac amyloidosis and VT/VF.

Patient selection, ventricular tachycardia substrate delineation and data transfer for stereotactic arrhythmia radioablation. A Clinical Consensus Statement of the European Heart Rhythm Association (EHRA) of the ESC and the Heart Rhythm Society (HRS).

Stereotactic arrythmia radioablation (STAR) is a novel, non-invasive and promising treatment option for ventricular arrythmias (VA). It has been applied in highly selected patients mainly as bail-out procedure, when (multiple) catheter-ablations, together with anti-arrhythmic drugs, were unable to control the VAs. Despite the increasing clinical use there is still limited knowledge of the acute and long-term response of normal and diseased myocardium to STAR. Acute toxicity appeared to be reasonably low but potential late adverse effects may be underreported. Among published studies, the provided methodological information is often limited, and patient selection, target volume definition, methods for determination and transfer of target volume, and techniques for treatment planning and execution differ across studies, hampering pooling of data and comparison across studies. In addition, STAR requires close and new collaboration between clinical electrophysiologists and radiation oncologists, which is facilitated by shared knowledge in each collaborator's area of expertise and a common language. This clinical consensus statement provides uniform definition of cardiac target volumes. It aims to provide advice in patient selection for STAR including etiology specific aspects, and advice in optimal cardiac target volume identification based on available evidence. Safety concerns and the advice for acute and long-term monitoring including the importance of standardized reporting and follow-up are covered by this document. Areas of uncertainty are listed, which require high-quality, reliable pre-clinical and clinical evidence before expansion of STAR beyond clinical scenarios in which proven therapies are ineffective or unavailable.

Retrograde coronary venous ethanol ablation for ventricular tachycardia in a patient with inaccessible substrate due to previous surgery.

INTRODUCTION: Catheter-based radiofrequency (RF) ablation is generally regarded as the standard approach for patients with ventricular tachycardia (VT) refractory to antiarrhythmic drug therapy and may be considered as a first-line approach when there is a preference to avoid these agents. Patients with a history of cardiac surgery may have VT substrate inaccessible to catheter ablation due to intervening prosthetic materials or scar. METHODS AND RESULTS: This article describes a 55-year-old patient with a history of surgically repaired subvalvular aortic stenosis and subsequent valve-sparing root replacement who presented with sustained VT. After RF ablation failed due to VT substrate "guarded" by graft material, retrograde coronary venous ethanol ablation (RCVEA) was employed to successfully treat the clinical VT. CONCLUSION: RCVEA ablation can be useful for treating VT when conventional ablation is limited by inaccessible substrate due to prior cardiac surgery.

Analysis of cancer cell line and tissue RNA sequencing data reveals an essential and dark matrisome.

Extracellular matrix remodeling is a hallmark of tissue development, homeostasis, and disease. The processes that mediate remodeling, and the consequences of such, are the topic of extensive focus in biomedical research. Cell culture methods represent a crucial tool utilized by those interested in matrisome function, the easiest of which are implemented with immortalized/cancer cell lines. These cell lines often form the foundations of a research proposal, or serve as vehicles of validation for other model systems. For these reasons, it is important to understand the complement of matrisome genes that are expressed when identifying appropriate cell culture models for hypothesis testing. To this end, we harvested bulk RNA sequencing data from the Cancer Cell Line Encyclopedia (CCLE) to assess matrisome gene expression in 1019 human cell lines. Our examination reveals that a large proportion of the matrisome is poorly represented in human cancer cell lines, with approximately 10% not expressed above threshold in any of the cell lines assayed. Conversely, we identify clusters of essential/common matrisome genes that are abundantly expressed in cell lines. To validate these observations against tissue data, we compared our findings with bulk RNA sequencing data from the Genotype-Tissue Expression (GTEx) portal and The Cancer Genome Atlas (TCGA) program. This comparison demonstrates general agreement between the "essential/common" and "dark/uncommon" matrisome across the three datasets, albeit with discordance observed in 59 matrisome genes between cell lines and tissues. Notably, all of the discordant genes are essential/common in tissues yet minimally expressed in cell lines, underscoring critical considerations for matrix biology researchers employing immortalized cell lines for their investigations.

Can Intracardiac Echocardiography Reduce Steam Pops During Half-Normal Saline Irrigated Radiofrequency Ablation?

BACKGROUND: Irrigated radiofrequency ablation with half-normal saline can potentially increase lesion size but may increase the risk of steam pops with the risk of emboli or perforation. We hypothesized that pops would be preceded by intracardiac echocardiography (ICE) findings as well as a large impedance fall. METHODS: In 100 consecutive patients undergoing endocardial ventricular arrhythmia radiofrequency ablation with half-normal saline, we attempted to observe the ablation site with ICE. Radiofrequency ablation power was titrated to a 15 to 20 Ohm impedance fall and could be adjusted for tissue whitening and increasing bubble formation on ICE. Steam pops were defined as audible or a sudden explosion of microbubbles on ICE. RESULTS: Of 2190 ablation applications in 100 patients (82% cardiomyopathy, 50% sustained ventricular tachycardia), pops occurred during 43 (2.0%) applications. Sites with pops had greater impedance decreases of 18 [14, 21]% versus 13 [10, 17]% (P<0.001). ICE visualized 1308 (59.7%) radiofrequency sites, and fewer pops occurred when ICE visualized the radiofrequency ablation site (1.4%) compared with without ICE visualization (2.8%; P=0.016). Of the 18 ICE-visible pops, 7 (39%) were silent but recognized as an explosion of bubbles on ICE. With ICE, 89% of pops were preceded by either tissue whitening or a sudden increase in bubbles. In a multivariable model, tissue whitening and a sudden increase in bubbles were associated with steam pops (odds ratio, 7.186; P=0.004, and odds ratio, 29.93; P<0.001, respectively), independent of impedance fall and power. There were no pericardial effusions or embolic events with steam pops. CONCLUSIONS: Steam pops occurred in 2% of half-normal saline radiofrequency applications titrated to an impedance fall and are likely under-recognized without ICE. On ICE, steam pops are usually preceded by tissue whitening or a sudden increase in bubble formation, which can potentially be used to adjust radiofrequency application to help reduce pops.

A randomized clinical trial of catheter ablation and antiarrhythmic drug therapy for suppression of ventricular tachycardia in ischemic cardiomyopathy: The VANISH2 trial.

BACKGROUND: Recurrent ventricular tachycardia (VT) in patients with prior myocardial infarction is associated with adverse quality of life and clinical outcomes, despite the presence of implanted defibrillators (ICDs). Suppression of recurrent VT can be accomplished with antiarrhythmic drug therapy or catheter ablation. The Ventricular Tachycardia Antiarrhythmics or Ablation In Structural Heart Disease 2 (VANISH2) trial is designed to determine whether ablation is superior to antiarrhythmic drug therapy as first line therapy for patients with ischemic cardiomyopathy and VT. METHODS: The VANISH2 trial enrolls patients with prior myocardial infarction and VT (with one of: ≥1 ICD shock; ≥3 episodes treated with antitachycardia pacing (ATP) and symptoms; ≥5 episodes treated with ATP regardless of symptoms; ≥3 episodes within 24 hours; or sustained VT treated with electrical cardioversion or pharmacologic conversion). Enrolled patients are classified as either sotalol-eligible, or amiodarone-eligible, and then are randomized to either catheter ablation or to that antiarrhythmic drug therapy, with randomization stratified by drug-eligibility group. Drug therapy, catheter ablation procedures and ICD programming are standardized. All patients will be followed until two years after randomization. The primary endpoint is a composite of mortality at any time, appropriate ICD shock after 14 days, VT storm after 14 days, and treated sustained VT below detection of the ICD after 14 days. The outcomes will be analyzed according to the intention-to-treat principle using survival analysis techniques RESULTS: The results of the VANISH2 trial are intended to provide data to support clinical decisions on how to suppress VT for patients with prior myocardial infarction. CLINICALTRIALS: gov registration NCT02830360.

Intramural needle ablation or repeated standard ablation in patients referred for repeat ablation of scar-related ventricular tachycardia.

INTRODUCTION: When ventricular tachycardia (VT) recurs after standard RF ablation (sRFA) some patients benefit from repeat sRFA, whereas others warrant advanced methods such as intramural needle ablation (INA). Our objectives are to assess the utility of repeat sRFA and to clarify the benefit of INA when repeat sRFA fails in patients with VT due to structural heart disease. METHODS: In consecutive patients who were prospectively enrolled in a study for INA for recurrent sustained monomorphic VT despite sRFA, repeat sRFA was considered first. INA was performed during the same procedure if repeat sRFA failed or no targets for sRFA were identified. RESULTS: Of 85 patients enrolled, acute success with repeat sRFA was achieved in 30 patients (35%), and during the 6-month follow-up, 87% (20/23) were free of VT hospitalization, 78% were free of any VT, and 7 were lost to follow-up. INA was performed in 55 patients (65%) after sRFA failed, or no endocardial targets were found abolished or modified inducible VT in 35/55 patients (64%). During follow-up, 72% (39/54) were free of VT hospitalization, 41% were free of any VT, and 1 was lost to follow-up. Overall, 59 out of 77 (77%) patients were free of hospitalization and 52% were free of any VT. Septal-origin VTs were more likely to need INA, whereas RV and papillary muscle VTs were less likely to require INA. CONCLUSIONS: Repeat sRFA was beneficial in 23% (18/77) of patients with recurrent sustained VT who were referred for INA. The availability of INA increased favorable outcomes to 52%.

Extracellular Proximity Labeling Reveals an Expanded Interactome for the Matrisome Protein TIMP2.

Classical methods of investigating protein-protein interactions (PPIs) are generally performed in non-living systems, yet in recent years new technologies utilizing proximity labeling (PL) have given researchers the tools to explore proximal PPIs in living systems. PL has distinct advantages over traditional protein interactome studies, such as the ability to identify weak and transient interactions in vitro and in vivo. Most PL studies are performed on targets within the cell or on the cell membrane. We have adapted the original PL method to investigate PPIs within the extracellular compartment, using both BioID2 and TurboID, that we term extracellular PL (ePL). To demonstrate the utility of this modified technique, we investigate the interactome of the widely expressed matrisome protein tissue inhibitor of metalloproteinases 2 (TIMP2). Tissue inhibitors of metalloproteinases (TIMPs) are a family of multi-functional proteins that were initially defined by their ability to inhibit the enzymatic activity of metalloproteinases (MPs), the major mediators of extracellular matrix (ECM) breakdown and turnover. TIMP2 exhibits a broad expression profile and is often abundant in both normal and diseased tissues. Understanding the functional transformation of matrisome regulators, like TIMP2, during the evolution of tissue microenvironments associated with disease progression is essential for the development of ECM-targeted therapeutics. Using carboxyl- and amino-terminal fusion proteins of TIMP2 with BioID2 and TurboID, we describe the TIMP2 proximal interactome. We also illustrate how the TIMP2 interactome changes in the presence of different stimuli, in different cell types, in unique culture conditions (2D vs 3D), and with different reaction kinetics (BioID2 vs. TurboID); demonstrating the power of this technique versus classical PPI methods. We propose that the screening of matrisome targets in disease models using ePL will reveal new therapeutic targets for further comprehensive studies.

Safety of ventricular arrhythmia radiofrequency ablation with half-normal saline irrigation.

AIMS: Failure of radiofrequency (RF) ablation of ventricular arrhythmias is often due to inadequate lesion size. Irrigated RF ablation with half-normal saline (HNS) has the potential to increase lesion size and reduce sodium delivery to the patient if the same volume of RF irrigant were used for normal saline (NS) and HNS but could increase risks related to steam pops and lesion size. This study aims to assess periprocedural complications and acute ablation outcome of ventricular arrhythmias ablation with HNS. METHODS AND RESULTS: Prospective assessment of outcomes was performed in 1024 endocardial and/or epicardial RF ablation procedures in 935 consecutive patients (median age 64 years, 71.2% men, 73.4% cardiomyopathy, 47.2% sustained ventricular tachycardia). Half-normal saline was selected at the discretion of the treating physician. Radiofrequency ablation power was generally titrated to a ≤15â€…Ω impedance fall with intracardiac echocardiography monitoring. Half-normal saline was used in 900 (87.9%) and NS in 124 (12.1%) procedures. Any adverse event within 30 days occurred in 13.0% of patients treated with HNS RF ablation including 4 (0.4%) strokes/transient ischaemic attacks and 34 (3.8%) pericardial effusions requiring treatment (mostly related to epicardial access). Two steam pops with perforation required surgical repair (0.2%). Patients who received NS irrigation had less severe disease and arrhythmias. In multivariable models, adverse events and acute success of the procedure were not related to the type of irrigation. CONCLUSION: Half-normal saline irrigation RF ablation with power guided by impedance fall and intracardiac echocardiography has an acceptable rate of complications and acute ablation success while administering half of the saline load expected for NS irrigation.

The TIMP protein family: diverse roles in pathophysiology.

The tissue inhibitors of matrix metalloproteinases (TIMPs) are a family of four matrisome proteins classically defined by their roles as the primary endogenous inhibitors of metalloproteinases (MPs). Their functions however are not limited to MP inhibition, with each family member harboring numerous MP-independent biological functions that play key roles in processes such as inflammation and apoptosis. Because of these multifaceted functions, TIMPs have been cited in diverse pathophysiological contexts. Herein, we provide a comprehensive overview of the MP-dependent and -independent roles of TIMPs across a range of pathological conditions. The potential therapeutic and biomarker applications of TIMPs in these disease contexts are also considered, highlighting the biomedical promise of this complex and often misunderstood protein family.

Multisize Electrode Field-of-View: Validation by High Resolution Gadolinium-Enhanced Cardiac Magnetic Resonance.

BACKGROUND: Voltage mapping to detect ventricular scar is important for guiding catheter ablation, but the field-of-view of unipolar, bipolar, conventional, and microelectrodes as it relates to the extent of viable myocardium (VM) is not well defined. OBJECTIVES: The purpose of this study was to evaluate electroanatomic voltage-mapping (EAVM) with different-size electrodes for identifying VM, validated against high-resolution ex-vivo cardiac magnetic resonance (HR-LGE-CMR). METHODS: A total of 9 swine with early-reperfusion myocardial infarction were mapped with the QDOT microcatheter. HR-LGE-CMR (0.3-mm slices) were merged with EAVM. At each EAVM point, the underlying VM in multisize transmural cylinders and spheres was quantified from ex vivo CMR and related to unipolar and bipolar voltages recorded from conventional and microelectrodes. RESULTS: In each swine, 220 mapping points (Q1, Q3: 216, 260 mapping points) were collected. Infarcts were heterogeneous and nontransmural. Unipolar and bipolar voltage increased with VM volumes from >175 mm3 up to >525 mm3 (equivalent to a 5-mm radius cylinder with height >6.69 mm). VM volumes in subendocardial cylinders with 1- or 3-mm depth correlated poorly with all voltages. Unipolar voltages recorded with conventional and microelectrodes were similar (difference 0.17 ± 2.66 mV) and correlated best to VM within a sphere of radius 10 and 8 mm, respectively. Distance-weighting did not improve the correlation. CONCLUSIONS: Voltage increases with transmural volume of VM but correlates poorly with small amounts of VM, which limits EAVM in defining heterogeneous scar. Microelectrodes cannot distinguish thin from thick areas of subendocardial VM. The field-of-view for unipolar recordings for microelectrodes and conventional electrodes appears to be 8 to 10 mm, respectively, and unexpectedly similar.

Stroke and Bleeding Risks of Endocardial Ablation for Ventricular Arrhythmias.

BACKGROUND: Risks of radiofrequency catheter ablation for ventricular arrhythmias include emboli and bleeding complications but data on antithrombotic regimens are limited and guidelines do not specify a systematic approach. OBJECTIVES: This study sought to assess embolic and bleeding complications in relation to pre-periprocedure and post-periprocedure antithrombotic regimens. METHODS: Prospective assessment for complications was performed for 663 endocardial radiofrequency catheter ablation procedures in 616 consecutive patients (median age 64 years [Q1-Q3: 54-73 years], 70.3% men, 71.6% with cardiomyopathy, 44.5% with sustained ventricular tachycardia). RESULTS: There were 2 strokes (0.3%; 95% CI: 0.0%-0.8%), 1 transient ischemic attack (0.15%), and 2 pulmonary emboli (0.3%). There were 39 bleeding complications (5.9%) including 11 pericardial effusions (1.7%), and 28 related to vascular access (4.2%). Consistent with the prevalence of coronary artery disease (47.5%), atrial fibrillation (30.0%), and prior stroke (10.6%), preprocedure, 464 patients (70.0%) were taking antithrombotic agents including 220 (33.2%) taking aspirin alone (ASA), and 163 (24.6%) taking warfarin or a direct acting oral anticoagulant (DOAC). Preprocedure non-ASA antiplatelet use (OR: 2.846; P = 0.011) and DOAC use (OR: 2.585; P = 0.032) were associated with risk of bleeding complications. Following ablation, 49.8% of patients were treated with ASA 325 mg/d and 30.3% received DOACs or warfarin. New DOAC or warfarin administration was initiated in only 6.6% of patients. Overall, 39.7% of patients continued the same preprocedure antithrombotic regimen. CONCLUSIONS: Stroke is a rare complication of radiofrequency catheter ablation for ventricular arrhythmia using ASA 325 mg/d as a minimal postprocedure regimen with more potent regimens for selected patients.

Tissue inhibitors of metalloproteinases are proteolytic targets of matrix metalloproteinase 9.

Extracellular proteolysis and turnover are core processes of tissue homeostasis. The predominant matrix-degrading enzymes are members of the Matrix Metalloproteinase (MMP) family. MMPs extensively degrade core matrix components in addition to processing a range of other factors in the extracellular, plasma membrane, and intracellular compartments. The proteolytic activity of MMPs is modulated by the Tissue Inhibitors of Metalloproteinases (TIMPs), a family of four multi-functional matrisome proteins with extensively characterized MMP inhibitory functions. Thus, a well-regulated balance between MMP activity and TIMP levels has been described as critical for healthy tissue homeostasis, and this balance can be chronically disturbed in pathological processes. The relationship between MMPs and TIMPs is complex and lacks the constraints of a typical enzyme-inhibitor relationship due to secondary interactions between various MMPs (specifically gelatinases) and TIMP family members. We illustrate a new complexity in this system by describing how MMP9 can cleave members of the TIMP family when in molar excess. Proteolytic processing of TIMPs can generate functionally altered peptides with potentially novel attributes. We demonstrate here that all TIMPs are cleaved at their C-terminal tails by a molar excess of MMP9. This processing removes the N-glycosylation site for TIMP3 and prevents the TIMP2 interaction with latent proMMP2, a prerequisite for cell surface MMP14-mediated activation of proMMP2. TIMP2/4 are further cleaved producing ∼14 kDa N-terminal proteins linked to a smaller C-terminal domain through residual disulfide bridges. These cleaved TIMP2/4 complexes show perturbed MMP inhibitory activity, illustrating that MMP9 may bear a particularly prominent influence upon the TIMP:MMP balance in tissues.