Anatomy and Pathology of the Cardiac Conduction System.

The cardiac conduction system is formed of histologically and electrophysiologically distinct specialized tissues uniquely located in the human heart. Understanding the anatomy and pathology of the cardiac conduction system is imperative to an interventional electrophysiologist to perform safe ablation and device therapy for the management of cardiac arrhythmias and heart failure. The current review summarizes the normal and developmental anatomy of the cardiac conduction system, its variation in the normal heart and congenital anomalies, and its pathology and discusses important clinical pearls for the proceduralist.

Single-Dose Intraprocedural Steroid Administration Does Not Impact Early Atrial Fibrillation Recurrence.

PURPOSE: To evaluate the effect of single-dose intravenous dexamethasone on atrial fibrillation (AF) recurrence following radiofrequency catheter ablation. METHODS: A cohort of 84 adult patients (> 18 years) underwent catheter ablation at Mayo Clinic Rochester from January to March 2019. Only first-time ablation patients were included, with all re-do ablations excluded to minimize heterogeneity. Administration of intraoperative dexamethasone 4 mg or 8 mg was determined by chart review from the procedure. At our institution, intraoperative intravenous steroids are administered for postoperative nausea and vomiting (PONV) prophylaxis at the discretion of the anesthesiologist. AF recurrence was determined by ECG or cardiac monitoring within 3 months or between 3 and 12 months post-ablation with an in-person follow-up visit. RESULTS: A total of 31 (36.9%) patients received intravenous dexamethasone compared to 54 (63.1%) who did not (approximating a 2:1 comparison group). The incidence of documented AF or atrial flutter, lasting greater than 30 s, within the first 3 months post-ablation was 29.0% in the dexamethasone group versus 24.5% in the non-dexamethasone group (p value 0.80). AF or atrial flutter recurrence at 3-12 months post-ablation was 3.2% in the dexamethasone group compared to 9.4% in the non-dexamethasone group (p value 0.41). CONCLUSION: These data suggest that intraoperative intravenous dexamethasone administered during AF ablation for postoperative nausea and vomiting prophylaxis may not have a significant effect on AF recurrence rates.

Substrate Characterization and Outcomes of Catheter Ablation of Ventricular Arrhythmias in Patients With Mitral Annular Disjunction.

BACKGROUND: Mitral annular disjunction (MAD) has recently been recognized as an arrhythmogenic entity. Data on the electrophysiological substrate as well as the outcomes of catheter ablation of ventricular arrhythmias in patients with MAD is limited. METHODS: Forty patients with MAD (mean age 47±15 years; 70% female) underwent catheter ablation for ventricular arrhythmias. Detailed clinical, electrocardiographic, cardiac imaging, and procedural data were collected. Clinical outcomes were compared between patients who had substrate modification in the MAD area and those who did not. RESULTS: Twenty-three (57.5%) patients had ablation for premature ventricular contractions, 10 (25%) patients for sustained ventricular tachycardia, and 7 (17.5%) patients for premature ventricular contraction-triggered ventricular fibrillation. Mean end-systolic MAD length was 10.58±3.49 mm on transthoracic echocardiography. Seventeen (42.5%) patients had preprocedural cardiac magnetic resonance imaging, and 5 (29%) patients had late gadolinium enhancement. Among the 18 (45%) patients who had abnormal local electrograms (low voltage, long-duration, fractionated, isolated mid-diastolic potentials) during electroanatomical mapping, 10 (25%) patients had abnormal electrograms in the anterolateral mitral annulus and/or MAD area. Substrate modification was performed in 10 (25%) patients. Catheter ablation was acutely successful in 36 (90%) patients (elimination of premature ventricular contraction or noninducibility of ventricular tachycardia). After a median follow-up duration of 54.08 (interquartile range, 10.67-89.79) months, premature ventricular contraction burden decreased from a median of 9.75% (interquartile range, 3.25-14) before the ablation to a median of 4% (interquartile range, 1-7.75) after the ablation (P=0.03 [95% CI, 0.055-6.5]). Eight (20.5%) patients had repeat ablation for ventricular arrhythmias. Substrate modification of the MAD was associated with a trend toward lower rates of repeat ablation (0% versus 26.7%; P=0.16). CONCLUSIONS: Patients with MAD have a complex arrhythmogenic substrate, and catheter ablation is effective in reducing recurrence of ventricular arrhythmias. Substrate mapping and ablation may be considered in these patients.

Anatomy and Pathology of the Cardiac Conduction System.

The cardiac conduction system is formed of histologically and electrophysiologically distinct specialized tissues uniquely located in the human heart. Understanding the anatomy and pathology of the cardiac conduction system is imperative to an interventional electrophysiologist to perform safe ablation and device therapy for the management of cardiac arrhythmias and heart failure. The current review summarizes the normal and developmental anatomy of the cardiac conduction system, its variation in the normal heart and congenital anomalies, and its pathology and discusses important clinical pearls for the proceduralist.

Catheter Ablation in Patients With Neuroendocrine (Carcinoid) Tumors and Carcinoid Heart Disease: Outcomes, Peri-Procedural Complications, and Management Strategies.

OBJECTIVES: This report describes a series of patients with neuroendocrine tumors with or without carcinoid heart disease undergoing catheter ablation at the authors' institution. BACKGROUND: Neuroendocrine (carcinoid) tumors are a rare form of neoplasm with the potential for systemic vasoactive effects and cardiac valvular involvement. These tumors can create peri-operative management challenges for the electrophysiologist. However, there are few data regarding ablation outcomes, periprocedural complications, and management of these patients. METHODS: All patients with neuroendocrine tumors undergoing catheter ablation at the Mayo Clinic, Rochester, Minnesota over a 25-year period were retrospectively reviewed. From this cohort, the type of arrhythmias ablated, the recurrence of arrhythmia, perioperative complications, and mortality were reviewed and analyzed. RESULTS: A total of 17 patients (52.9% male; mean age 62.4 ± 9.3 years) with neuroendocrine tumors underwent catheter ablation during the study period. Primary tumor sites included the gastrointestinal tract (n = 11), lung (n = 4), ovary (n = 1), and lymph node (n = 1). Nine patients had metastatic disease, 5 of whom were on somatostatin analog therapy at the time of ablation. Three patients had active symptoms of carcinoid syndrome at the time of ablation, and 2 of those patients had carcinoid heart disease. Ablations were performed mainly for atrial arrhythmias (76.5%): atrioventricular nodal re-entry tachycardia (n = 7), atrial fibrillation (n = 4), and atrial flutter (n = 2). Four patients underwent ablation of ventricular arrhythmias. During a mean follow-up of 19.2 ± 26.2 months, arrhythmia recurred in 35.3% of patients. Three patients (17.6%) had periprocedural complications: pericardial effusion (n = 1), groin site hematoma (n = 1), and carcinoid crisis (n = 1). No deaths were noted in the peri-operative period. CONCLUSIONS: In a unique cohort of patients with neuroendocrine tumors, catheter ablation was feasible in patients with or without carcinoid syndrome. Carcinoid crisis may occur during the periprocedural period, which can be life-threatening, and a specified protocol for management is important to mitigate this risk.

Arrhythmias Associated with Inflammatory Cardiomyopathies.

PURPOSE OF REVIEW: To provide an approach to the diagnosis and treatment of arrhythmias associated with inflammatory cardiomyopathies. RECENT FINDINGS: Inflammatory cardiomyopathies are increasingly recognized as the etiology of both ventricular and supraventricular arrhythmias. There have been recent studies providing novel insights into the pathogenesis of arrhythmias in inflammatory cardiomyopathies and exploring the role of various diagnostic tools and treatment strategies. SUMMARY: Patients with inflammatory cardiomyopathies often present with one or more arrhythmias, including atrioventricular block, atrial and ventricular tachyarrhythmias, and occasionally sudden cardiac death. Given dynamic pathophysiology and heterogeneous presentation, the management of arrhythmias in these patients presents unique challenges. We review the current approach to the diagnosis and treatment of arrhythmias in this challenging cohort of patients with an emphasis on cardiac sarcoidosis. SUPPLEMENTARY INFORMATION: The online version of this article (10.1007/s11936-020-00871-5) contains supplementary material, which is available to authorized users.

Implantation of leadless pacemakers via inferior vena cava filters is feasible and safe: Insights from a multicenter experience.

BACKGROUND: The leadless Micra transcatheter-pacing system (Micra-TPS) is implanted via a femoral approach using a 27-French introducer sheath. The Micra Transcutaneous Pacing Study excluded patients with inferior vena cava (IVC) filters. OBJECTIVE: To examine the feasibility and safety of Micra-TPS implantation through an IVC filter. METHODS: This multicenter retrospective study included patients with an IVC filter who underwent a Micra-TPS implantation. Data for clinical and IVC filter characteristics, preprocedure imaging, and procedural interventions were collected. The primary outcome was a successful leadless pacemaker (LP) implantation via a femoral approach in the presence of an IVC filter. Periprocedural and delayed clinical complications were also evaluated. RESULTS: Of the 1528 Micra-TPS implants attempted, 23 patients (1.5%) had IVC filters. The majority (69.6%) of IVC filters were permanent. Six (26.1%) patients underwent preprocedural imaging to assess for filter patency. One patient's filter was retrieved before LP implantation. The primary outcome was achieved in 21 of 22 patients (95.5%) with an existing IVC filter. An occluded IVC precluded LP implantation in one patient. Difficulty advancing the stiff guidewire or the 27-Fr sheath was encountered in five patients. These cases required repositioning of the wire (n = 2), gradual sheath upsizing (n = 2), or balloon dilation of the filter (n = 1). Postprocedure fluoroscopy revealed intact filters in all cases. During a median 6-month follow-up, there were no clinical complications related to the filter or the Micra-TPS. CONCLUSION: This multicenter experience demonstrates the feasibility and safety of Micra-TPS implantation via an IVC filter without acute procedural or delayed clinical complications.

The Future of Percutaneous Epicardial Interventions.

The pericardial space provides a unique vantage point to access different cardiac structures for diagnosis and treatment of arrhythmias and other nonelectrophysiologic conditions, such as heart failure. There have been notable innovations to improve safety of percutaneous pericardial access and its use for various procedures. Percutaneous pericardial device therapies for pacing and defibrillation have been in development, success of which will be a significant advance in treatment of bradyarrhythmias, cardiac resynchronization therapy, and prevention of arrhythmic deaths. There is need for continued efforts in development and expansion of this technique and a systematic approach to monitor efficacy and safety outcomes.

Ventricular asystole in the presence of a biventricular device.

In pacemaker-dependent patients with a newly implanted cardiac device, acute lead dislodgement constitutes one of the most common causes of loss of capture and ventricular asystole. In a biventricular system, it would be expected that such a potentially catastrophic event would be prevented with back-up right ventricular pacing unless both leads dislodge.

Elevated end-diastolic wall stress after acute myocardial infarction predicts adverse cardiovascular outcomes and longer hospital length of stay.

BACKGROUND: Acute myocardial infarction (MI) leads to ventricular remodeling in response to oxygen demand. Such changes include left ventricular (LV) dilatation and increased myocardial wall stress. Prior studies showed that wall stress is a vital parameter of cardiac remodeling. However, outcome data are lacking. We aim to investigate wall stress post-MI in relation to biomarkers of cardiac remodeling and cardiovascular outcomes. METHODS: Patients presenting with ST-elevation MI (STEMI) requiring primary percutaneous intervention (PCI) were enrolled prospectively. LVEF and volume-based end-diastolic (EDWS) and end-systolic (ESWS) wall stress were measured from predischarge echocardiograms. Serum samples were collected for measurement of serum biomarkers. We identified 81 patients meeting inclusion criteria (64% men, 36% women) with a mean age of 61. The primary outcome was major adverse cardiovascular events (MACE) defined as 1-year composite endpoint of cardiac mortality, recurrent MI, revascularization, or stroke. Length of hospitalization (LOH) was recorded. RESULTS: Major adverse cardiovascular events-positive patients (n = 12) had significantly higher EDWS levels (15.87 vs 12.33, P = 0.045), and galectin-3 levels (19.07 vs 11.75, P = 0.015), and lower LVEF (40.0% vs 48.4%, P = 0.023) compared to MACE-negative patients. Patients with LOH > 72 hours (n = 33) had significantly higher EDWS, galectin-3, and peak troponin, and lower LVEF compared to patients with LOH < 72 hours. EDWS positively correlated with LOH and galectin-3. EDWS was an independent predictor of MACE by binomial regression analysis. CONCLUSION: End-diastolic walls tress is a potential prognostic tool for risk stratifying STEMI patients, providing an assessment of the functional consequences of myocardial remodeling. It is predictive of MACE independent of LVEF, associated with longer hospitalizations, and correlates with galectin-3, a biomarker of cardiac remodeling.

The Therapeutic Potential of Blocking Galectin-3 Expression in Acute Myocardial Infarction and Mitigating Inflammation of Infarct Region: A Clinical Outcome-Based Translational Study.

INTRODUCTION: Increased galectin-3 is associated with ischemic cardiomyopathy, although its role in early remodeling post-myocardial infarction (MI) has not been fully elucidated. There are no data demonstrating that blocking galectin-3 expression would have an impact on the heart and that its relationship to remodeling is not simply an epiphenomenon. The direct association between galectin-3 and myocardial inflammation, dysfunction, and adverse cardiovascular outcomes post-MI was examined using clinical and translational studies. METHODS: We performed expression analysis of 9753 genes in murine model of acute MI. For galectin-3 loss of function studies, homozygous galectin-3 knock-out (KO) mice were subjected to coronary artery ligation procedure to induce acute MI (MI, N = 6; Sham, N = 6). For clinical validation, serum galectin-3 levels were measured in 96 patients with ST-elevation MI. Echocardiographic and angiographic parameters of myocardial dysfunction and 3-month composite outcome including mortality, recurrent MI, stroke, and heart failure hospitalization were measured. RESULTS: In the infarct regions of murine models, galectin-3 was a robustly expressed gene. Elevated galectin-3 expression strongly correlated with macrophage-mediated genes. Galectin-3 KO mice showed reduced myocardial macrophage infiltration after acute MI. Galectin-3 levels were higher in patients with early systolic dysfunction, and predicted 3-month major adverse cardiovascular events (area under the curve [AUC]: 0.917 ± 0.063; P = .001). CONCLUSIONS: Galectin-3 is directly associated with early myocardial inflammation post-MI and may represent a potential target for therapeutic inhibition.

Arrhythmias in Patients ≥80 Years of Age: Pathophysiology, Management, and Outcomes.

Advances in medical care have led to an increase in the number of octogenarians and even older patients, forming an important and unique patient subgroup. It is clear that advancing age is an independent risk factor for the development of most arrhythmias, causing substantial morbidity and mortality. Patients ≥80 years of age have significant structural and electrical remodeling of cardiac tissue; accrue competing comorbidities; react differently to drug therapy; and may experience falls, frailty, and cognitive impairment, presenting significant therapeutic challenges. Unfortunately, very old patients are under-represented in clinical trials, leading to critical gaps in evidence to guide effective and safe treatment of arrhythmias. In this state-of-the-art review, we examine the pathophysiology of aging and arrhythmias and then present the available evidence on age-specific management of the most common arrhythmias, including drugs, catheter ablation, and cardiac implantable electronic devices.

High-risk carotid plaques identified by CT-angiogram can predict acute myocardial infarction.

Prior studies identified the incremental value of non-invasive imaging by CT-angiogram (CTA) to detect high-risk coronary atherosclerotic plaques. Due to their superficial locations, larger calibers and motion-free imaging, the carotid arteries provide the best anatomic access for the non-invasive characterization of atherosclerotic plaques. We aim to assess the ability of predicting obstructive coronary artery disease (CAD) or acute myocardial infarction (MI) based on high-risk carotid plaque features identified by CTA. We retrospectively examined carotid CTAs of 492 patients that presented with acute stroke to characterize the atherosclerotic plaques of the carotid arteries and examined development of acute MI and obstructive CAD within 12-months. Carotid lesions were defined in terms of calcifications (large or speckled), presence of low-attenuation plaques, positive remodeling, and presence of napkin ring sign. Adjusted relative risks were calculated for each plaque features. Patients with speckled (<3 mm) calcifications and/or larger calcifications on CTA had a higher risk of developing an MI and/or obstructive CAD within 1 year compared to patients without (adjusted RR of 7.51, 95%CI 1.26-73.42, P = 0.001). Patients with low-attenuation plaques on CTA had a higher risk of developing an MI and/or obstructive CAD within 1 year than patients without (adjusted RR of 2.73, 95%CI 1.19-8.50, P = 0.021). Presence of carotid calcifications and low-attenuation plaques also portended higher sensitivity (100 and 79.17%, respectively) for the development of acute MI. Presence of carotid calcifications and low-attenuation plaques can predict the risk of developing acute MI and/or obstructive CAD within 12-months. Given their high sensitivity, their absence can reliably exclude 12-month events.

Defining "mutation" and "polymorphism" in the era of personal genomics.

BACKGROUND: The growing advances in DNA sequencing tools have made analyzing the human genome cheaper and faster. While such analyses are intended to identify complex variants, related to disease susceptibility and efficacy of drug responses, they have blurred the definitions of mutation and polymorphism. DISCUSSION: In the era of personal genomics, it is critical to establish clear guidelines regarding the use of a reference genome. Nowadays DNA variants are called as differences in comparison to a reference. In a sequencing project Single Nucleotide Polymorphisms (SNPs) and DNA mutations are defined as DNA variants detectable in >1 % or <1 % of the population, respectively. The alternative use of the two terms mutation or polymorphism for the same event (a difference as compared with a reference) can lead to problems of classification. These problems can impact the accuracy of the interpretation and the functional relationship between a disease state and a genomic sequence. We propose to solve this nomenclature dilemma by defining mutations as DNA variants obtained in a paired sequencing project including the germline DNA of the same individual as a reference. Moreover, the term mutation should be accompanied by a qualifying prefix indicating whether the mutation occurs only in somatic cells (somatic mutation) or also in the germline (germline mutation). We believe this distinction in definition will help avoid confusion among researchers and support the practice of sequencing the germline and somatic tissues in parallel to classify the DNA variants thus defined as mutations.

Class III ß-tubulin in normal and cancer tissues.

Microtubules are polymeric structures composed of tubulin subunits. Each subunit consists of a heterodimer of α- and ß-tubulin. At least seven ß-tubulin isotypes, or classes, have been identified in human cells, and constitutive isotype expression appears to be tissue specific. Class III ß-tubulin (ßIII-tubulin) expression is normally confined to testes and tissues derived from neural cristae. However, its expression can be induced in other tissues, both normal and neoplastic, subjected to a toxic microenvironment characterized by hypoxia and poor nutrient supply. In this review, we will summarize the mechanisms underlying ßIII-tubulin constitutive and induced expression. We will also illustrate its capacity to serve as a biomarker of neural commitment in normal tissues and as a pure prognostic biomarker in cancer patients.

Taxanes in combination with biologic agents for ovarian and breast cancers.

Taxane-based cytotoxic therapy is commonly prescribed for breast and ovarian cancers. Although these cancers are often sensitive to such therapy, clinical benefit and overall survival are limited owing to the development of chemoresistance and recurrence. Biologic agents that specifically target proteins of growth factor signaling pathways, which are hyperactivated in cancers, offer attractive targets for cancer therapeutics and may work synergistically with standard taxane-based chemotherapy to improve patient outcomes. We review clinical trials of biologic agents--angiogenic, tyrosine kinase, and antibody inhibitors--in combination with taxane-based therapy for ovarian and breast cancers. Many clinical trials have shown promising results. However, some biologic agents still need larger trials to assess safety and efficacy. As research into the heterogeneity and complexity of ovarian and breast cancers improves our understanding of the molecular pathways involved, there is no question that targeted therapies with biologic agents will expand the future array of available cancer therapeutics.

Kaposi's sarcoma-associated herpesvirus K3 and K5 proteins down regulate both DC-SIGN and DC-SIGNR.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of multicentric Castleman's disease, primary effusion lymphoma and Kaposi's sarcoma. In this study, we show that like the C-type lectin DC-SIGN, the closely related DC-SIGNR can also enhance KSHV infection. Following infection, they are both targeted for down modulation and our data indicate that the KSHV MARCH-family ubiquitin ligase K5 is mediating this regulation and subsequent targeting for degradation of DC-SIGN and DC-SIGNR in the context of the virus. The closely related viral K3 protein, is also able to target these lectins in exogenous expressions studies, but only weakly during viral infection. In addition to requiring a functional RING-CH domain, several protein trafficking motifs in the C-terminal region of both K3 and K5 are important in regulation of DC-SIGN and DC-SIGNR. Further exploration of this modulation revealed that DC-SIGN is endocytosed from the cell surface in THP-1 monocytes, but degraded from an internal location with minimal endocytosis in HEK-293 cells. Pull-down data indicate that both K3 and K5 preferentially associate with immature forms of the lectins, mediating their ubiquitylation and degradation. Together, these data emphasize the molecular complexities of K3 and K5, while expanding the repertoire of targets of these two viral proteins.