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.

Intracardiac thrombi fluttering like hair in the wind at VT ablation.

INTRODUCTION: Intracardiac echocardiography (ICE) reveals mobile thrombus on implantable electronic device leads in some patients undergoing electrophysiologic procedures. METHODS: ICE was performed in a patient undergoing ventricular tachycardia (VT) ablation. RESULTS: ICE showed extensive mobile thrombi on the implantable cardioverter defibrillator lead. Radiofrequency catheter ablation of VT from perimitral scar was safely performed via a retrograde aortic approach. After the procedure, chronic anticoagulation was initiated. CT-angiography of the chest 2 months later showed no pulmonary emboli. CONCLUSIONS: The significance of these thrombi, as related to chronic pulmonary embolization, warrants further study.

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.

The Continuing Saga of Tissue Inhibitor of Metalloproteinase 2: Emerging Roles in Tissue Homeostasis and Cancer Progression.

Tissue inhibitors of metalloproteinases (TIMPs) are a conserved family of proteins that were originally identified as cytokine-like erythroid growth factors. Subsequently, TIMPs were characterized as endogenous inhibitors of matrixin proteinases. These proteinases are the primary mediators of extracellular matrix turnover in pathologic conditions, such as cancer invasion and metastasis. Thus, TIMPs were immediately recognized as important regulators of tissue homeostasis. However, TIMPs also demonstrate unique biological activities that are independent of metalloproteinase regulation. Although often overlooked, these non-protease-mediated TIMP functions demonstrate a variety of direct cellular effects of potential therapeutic value. TIMP2 is the most abundantly expressed TIMP family member, and ongoing studies show that its tumor suppressor activity extends beyond protease inhibition to include direct modulation of tumor, endothelial, and fibroblast cellular responses in the tumor microenvironment. Recent data suggest that TIMP2 can suppress both primary tumor growth and metastatic niche formation. TIMP2 directly interacts with cellular receptors and matrisome elements to modulate cell signaling pathways that result in reduced proliferation and migration of neoplastic, endothelial, and fibroblast cell populations. These effects result in enhanced cell adhesion and focal contact formation while reducing tumor and endothelial proliferation, migration, and epithelial-to-mesenchymal transitions. These findings are consistent with TIMP2 homeostatic functions beyond simple inhibition of metalloprotease activity. This review examines the ongoing evolution of TIMP2 function, future perspectives in TIMP research, and the therapeutic potential of TIMP2.

Cardiac Sarcoidosis and a Likely Pathogenic TTN Variant in a Patient Presenting With Ventricular Tachycardia.

Rare variants in TTN are the most common monogenic cause of early-onset atrial fibrillation and dilated cardiomyopathy. Whereas cardiac sarcoidosis is very underdiagnosed, a common presentation can be ventricular arrhythmias. This report presents a patient with a likely pathogenic TTN variant and cardiac sarcoidosis. (Level of Difficulty: Intermediate.).

Diagnostic Impact and Prognostic Value of Cardiac Magnetic Resonance in Patients With Ventricular Arrhythmias.

BACKGROUND: Cardiac magnetic resonance (CMR) characterizes myocardial substrate relevant to sudden cardiac death (SCD). However, its clinical value in patients presenting with ventricular arrhythmias is still being defined. OBJECTIVES: The authors sought to examine the diagnostic and prognostic value of multiparametric CMR in a cohort of consecutive patients referred for assessment of ventricular arrhythmias. METHODS: Consecutive patients undergoing CMR for nonsustained ventricular tachycardia (NSVT) (n = 345) or sustained ventricular tachycardia (VT)/aborted SCD (n = 297) were followed over a median of 4.4 years. Major adverse cardiac events included death, recurrent VT/ventricular fibrillation requiring therapy, and hospitalization for congestive heart failure. RESULTS: Of the 642 patients, 256 were women (40%), mean age was 54 ± 15 years, and median left ventricular ejection fraction was 58% (IQR: 49%-63%). A structurally abnormal heart by CMR assessment was detected in 40% of patients with NSVT and 66% in those with VT/SCD (P < 0.001). CMR assessment yielded a diagnostic change in 27% of NSVT patients vs 41% of those with VT/SCD (P < 0.001). During follow-up, 51 patients (15%) with NSVT and 104 patients (35%) with VT/SCD experienced major adverse cardiac events (MACE). An abnormal CMR was associated with a higher annual rate for MACE for both NSVT (0.7% vs 7.7%; P < 0.001) and VT/SCD (3.8% vs 13.3%; P < 0.001) patients. In a multivariate model including left ventricular ejection fraction, an abnormal CMR remained strongly associated with MACE in NSVT (HR: 5.23 [95% CI: 2.28-12.0]; P < 0.001) and VT/SCD (HR: 1.88 [95% CI: 1.07-3.30]; P = 0.03). Adding CMR assessment to the multivariable model for MACE yielded a significant improvement in the integrated discrimination improvement and an improvement in the C-statistic in the NSVT cohort. CONCLUSIONS: In patients presenting with ventricular arrhythmias, multiparametric CMR assessment provides diagnostic clarification and effective risk stratification beyond current standard of care.