Rates of pulmonary vein reconnection at repeat ablation for recurrent atrial fibrillation and its impact on outcomes among females and males.

BACKGROUND: Several studies have demonstrated that females have a higher risk of arrhythmia recurrence after pulmonary vein (PV) isolation for atrial fibrillation (AF). There are limited data on sex-based differences in PV reconnection rates at repeat ablation. We aimed to investigate sex-based differences in electrophysiological findings and atrial arrhythmia recurrence after repeat AF ablation METHODS: We conducted a retrospective study of 161 consecutive patients (32% female, age 65 ± 10 years) who underwent repeat AF ablation after index PV isolation between 2010 and 2022. Demographics, procedural characteristics and follow-up data were collected. Recurrent atrial tachycardia (AT)/AF was defined as any atrial arrhythmia ≥30 s in duration. RESULTS: Compared to males, females tended to be older and had a significantly higher prevalence of prior valve surgery (10 vs. 2%; P = .03). At repeat ablation, PV reconnection was found in 119 (74%) patients. Males were more likely to have PV reconnection at repeat ablation compared to females (81 vs. 59%; P = .004). Excluding repeat PV isolation, there were no significant differences in adjunctive ablation strategies performed at repeat ablation between females and males. During follow-up, there were no significant differences in freedom from AT/AF recurrence between females and males after repeat ablation (63 vs. 59% at 2 years, respectively; P = .48). CONCLUSIONS: After initial PV isolation, significantly fewer females have evidence of PV reconnection at the time of repeat ablation for recurrent AF. Despite this difference, long-term freedom from AT/AF was similar between females and males after repeat ablation.

Role of plakophilin-2 expression on exercise-related progression of arrhythmogenic right ventricular cardiomyopathy: a translational study.

AIMS: Exercise increases arrhythmia risk and cardiomyopathy progression in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients, but the mechanisms remain unknown. We investigated transcriptomic changes caused by endurance training in mice deficient in plakophilin-2 (PKP2cKO), a desmosomal protein important for intercalated disc formation, commonly mutated in ARVC and controls. METHODS AND RESULTS: Exercise alone caused transcriptional downregulation of genes coding intercalated disk proteins. The changes converged with those in sedentary and in exercised PKP2cKO mice. PKP2 loss caused cardiac contractile deficit, decreased muscle mass and increased functional/transcriptomic signatures of apoptosis, despite increased fractional shortening and calcium transient amplitude in single myocytes. Exercise accelerated cardiac dysfunction, an effect dampened by pre-training animals prior to PKP2-KO. Consistent with PKP2-dependent muscle mass deficit, cardiac dimensions in human athletes carrying PKP2 mutations were reduced, compared to matched controls. CONCLUSIONS: We speculate that exercise challenges a cardiomyocyte "desmosomal reserve" which, if impaired genetically (e.g., PKP2 loss), accelerates progression of cardiomyopathy.

Adding the Cancer Genome Atlas Chromosome Classes to American Joint Committee on Cancer System Offers More Precise Prognostication in Uveal Melanoma.

PURPOSE: Uveal melanoma (UM) is a rare disease and the most common primary intraocular malignancy in adults, with a high risk of metastases. Reliable prognostication systems are based on anatomic features, as in the tumor-node-metastasis staging of the American Joint Committee on Cancer (AJCC) system, or on genetic information, as in The Cancer Genome Atlas (TCGA) system. Prior evidence suggests that combining both systems may be beneficial. We evaluated the benefit of combining the TCGA and AJCC systems in a large cohort of patients. DESIGN: Retrospective case series of patients with UM. PARTICIPANTS: Nine hundred seventy-nine patients with a choroidal or ciliary body melanoma treated at the Wills Eye Hospital between 1998 and 2020, 94% of whom received eye-sparing treatment. METHODS: Tumors were classified into 4 TCGA groups based on chromosome copy number: A (disomy 3, normal 8q), B (disomy 3, any 8q gain), C (monosomy 3, 1 extra copy of 8q), and D (monosomy 3, multiple 8q gain). The eighth edition of the AJCC staging manual was used for AJCC staging. Cox regression and the log-rank test were used for survival analysis. MAIN OUTCOME MEASURE: Metastasis-free survival. RESULTS: Combining information of the 2 systems improved prognostication in intermediate groups: in TCGA group C, we saw an increased rate of metastasis in AJCC stage III (28%) compared with stage II (8.9%); the same was seen in AJCC stage II, going from TCGA group C (8.9%) to group D (46%), and in AJCC stage III, going from group C (28%) to group D (49%). In patients with AJCC stage II or III disease, loss of chromosome 3 and gain of 8q (TCGA groups C and D) significantly worsened the prognosis, with multiple 8q gain (TCGA group D) having a greater impact. CONCLUSIONS: Combining information from AJCC stages and TCGA groups yields a better predictive power even in this set of relatively small tumors. We propose that physicians take both systems into account whenever possible, especially in moderate-risk groups.

Chromosome 3 and 8q Aberrations in Uveal Melanoma Show Greater Impact on Survival in Patients with Light Iris versus Dark Iris Color.

PURPOSE: Individuals with gray, blue, or green eyes have a higher chance of developing uveal melanoma (UM) than those with brown eyes. We wondered whether iris pigmentation might be related not only to predisposition to UM but also to its behavior; therefore, we compared the clinical, histopathologic, and genetic characteristics of UM between eyes with different colors. DESIGN: We determined iris color in a large cohort of patients enucleated for UM. Clinical and histopathologic tumor characteristics, chromosome status, and survival were compared among 3 groups on the basis of iris color. PARTICIPANTS: A total of 412 patients with choroidal/ciliary body UM, who had undergone primary enucleation at the Leiden University Medical Center, Leiden, The Netherlands, between 1993 and 2019, were divided into 3 groups based on iris color: gray/blue, green/hazel, and brown. The validation cohort included 934 patients with choroidal/ciliary body UM treated at Wills Eye Hospital (WEH). METHODS: Comparison of clinical, histopathologic, and genetic characteristics of UM in patients with different iris colors. MAIN OUTCOME MEASURES: Melanoma-related survival in UM patients, divided over 3 iris color groups, in relation to the tumor's chromosome 3 and 8q status. RESULTS: Moderate and heavy tumor pigmentations were especially seen in eyes with a brown iris (P < 0.001). Survival did not differ between patients with different iris colors (P = 0.27); however, in patients with a light iris, copy number changes in chromosome 3 and 8q had a greater influence on survival than in patients with a dark iris. Likewise, chromosome 3 and chromosome 8q status affected survival more among patients with lightly pigmented tumors than in patients with heavily pigmented tumors. The WEH cohort similarly showed a greater influence of chromosome aberrations in light-eyed individuals. CONCLUSIONS: Although iris color by itself did not relate to UM-related survival, chromosome 3 and 8q aberrations had a larger influence on survival in patients with a light iris than those with a brown iris. This suggests a synergistic effect of iris pigmentation and chromosome status in the regulation of oncogenic behavior of UM. Iris color should be taken into consideration when calculating a patient's risk for developing metastases.

Impact of great auricular nerve sacrifice on sensory disturbance after parotidectomy.

PURPOSE: To investigate the association between great auricular nerve (GAN) sacrifice during parotidectomy and postoperative sensory disturbance. MATERIALS AND METHODS: Patients who underwent parotidectomy between November 2016 and May 2020 at a single academic institution were included in this retrospective chart review. Operative notes were reviewed to determine incidence of GAN sacrifice. Prevalence of patient-reported sensory complaints in the GAN distribution and time to spontaneous resolution of symptoms were assessed. RESULTS: Of 305 parotidectomy patients, 111 (36.4%) endorsed complaints of postoperative sensory disturbances in the GAN distribution typically characterized by numbness or shooting pains. GAN sacrifice was present in 9 (8.1%) of 111 patients who experienced sensory disturbances compared to 9 (4.6%) who reported no sensory disturbances (p > 0.05). Twenty-five patients (32.5%) experienced spontaneous resolution of symptoms at their most recent follow-up at a mean of 6.2 months after onset of symptoms. Of those that experienced a sensory disturbance, GAN preservation was not significantly associated with likelihood of spontaneous recovery (p > 0.05). CONCLUSIONS: We report the largest series to date of post-operative sensory disturbance in parotidectomy patients as it relates to intraoperative GAN sacrifice. Although the relationship between GAN sacrifice and the incidence of postoperative sensory disturbance and its subsequent resolution were not significant, we continue to advocate for GAN preservation to reduce incidence of postoperative sensory disturbances.

Rate of Fat Graft Volume Loss After Parotidectomy.

BACKGROUND: Reconstruction after parotidectomy can include fat grafting, which allows for symmetry, but grafts have demonstrated volume loss over time. OBJECTIVES: To provide quantitative evidence for the rate of volume loss of fat grafts. METHODS: Patients who received parotidectomy with fat graft reconstruction at a single institution from August 2016 to October 2020 were identified. Relationships between clinical factors and the logarithmic rate of fat graft volume loss were analyzed. RESULTS: Twelve patients received parotidectomy, fat graft reconstruction, and underwent a postoperative magnetic resonance imaging (MRI) scan. Rate of fat graft volume loss was a mean of 1.8% per month (standard deviation [SD]: 2.1% per month). Total parotid fat graft volume loss was a mean of 57.4% (SD: 67.5%). The mean follow-up time was 35.5 months (range: 9-89.8 months). Correlations between body mass index (BMI), history of smoking, and history of alcohol consumption and logarithmic rates of fat graft volume loss were increased but not significantly. CONCLUSIONS: Fat grafts have the potential of 60% volume loss at approximately 1 year. If there is clinical suspicion that patients will require adjuvant radiation or have clinical factors such as a smoking or alcohol-use history, volume requirements may be even greater to maintain adequate parotid volume for aesthetic purposes.

Noncirrhotic portal hypertension in primary biliary cholangitis with coexisting CREST syndrome.

Primary Biliary Cholangitis (PBC) is an autoimmune liver disease that is sometimes associated with CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome. If left untreated, PBC eventually progresses to liver cirrhosis. We describe an adult patient with CREST-PBC who presented with recurrent variceal bleeding and ultimately required transjugular intrahepatic portosystemic shunt (TIPS) insertion. Liver biopsy excluded cirrhosis, resulting in a diagnosis of noncirrhotic portal hypertension. This case report describes the pathophysiology of presinusoidal portal hypertension as a rare complication of PBC and its association with coexisiting CREST.

Combination cryotherapy and intralesional corticosteroid versus steroid monotherapy in the treatment of keloids.

BACKGROUND: Keloids are common and have significant negative effects on quality of life. There is a need for more effective treatment approaches for keloids. AIMS: We investigated treatment outcomes of intralesional triamcinolone acetonide (IL TAC) compared with combination IL TAC and cryotherapy, including changes in pruritus, pain, and keloid size. PATIENTS/METHODS: We performed a prospective study of patients referred to one provider who treated patients with combination therapy and compared them to a historic control cohort treated with IL TAC alone. All patients were seen at Thomas Jefferson University between 2019 and 2021. Patient demographics, location of keloids, and inciting events were recorded. Pruritus and pain scores were self-reported by patients using a 10-point Likert scale administered as standard of care. Changes in keloid size were denoted as "No change," "up to 50% decrease," "more than 50% decrease," and "completely flattened." RESULTS: While both treatments produced a significant reduction in mean pruritus and pain scores, there was no difference between the two treatment groups (p = 0.3933 and p = 0.2123, respectively). A greater percentage of keloids in the combination therapy group had a post-treatment size difference greater than 50% compared with those in the IL TAC only treatment group (p = 0.0021). In the subgroup of pubic keloids, all lesions treated with combination IL TAC and cryotherapy responded remarkably well to treatment. CONCLUSIONS: While both IL TAC and IL TAC with cryotherapy were effective at reducing pruritus and pain, combination therapy was more effective in reducing keloid size, specifically for pubic keloids.

Surgical ventricular reconstruction for ischemic cardiomyopathy-a systematic review and meta-analysis of 7,685 patients.

Background: Surgical ventricular reconstruction (SVR) has been used to control adverse ventricular remodeling and improve cardiac function in ischemic cardiomyopathy. The purpose of this systematic review and meta-analysis was to collect and analyze all available evidence on the utilization and efficacy of SVR. Methods: An electronic database search was performed to identify all retrospective and prospective studies on SVR for ischemic cardiomyopathy in the English literature from 2000 through 2020. A total of 92 articles with a collective 7,685 patients undergoing SVR were included in the final analysis. Results: The mean patient age was 61 years (95% CI: 59-63) and 80% (78-82%) were male. Congestive heart failure was present in 66% (54-78%) and angina in 58% (45-70%). Concomitant coronary artery bypass grafting was undertaken in 92% (90-93%) while 21% (18-24%) underwent mitral valve repair. Pre vs. post-SVR, significant improvement was seen in left ventricular ejection fraction (LVEF) [29.9% (28.8-31.2%) vs. 40.9% (39.4-42.4%), P<0.01], left ventricular end-systolic (LVESD) and end-diastolic diameters (LVEDD) [LVESD: 49.9 mm (48.1-51.7) vs. 45 mm (42.8-47.3), P<0.01, LVEDD: 63.8 mm (62-65.6) vs. 58.23 mm (56.6-60), P<0.01], and left ventricular end-systolic (LVESVI) and end-diastolic volume indices (LVEDVI) [LVESVI: 83.9 mL/m2 (79.3-88.4) vs. 46.8 mL/m2 (43.5-50.1), P<0.01; LVEDVI: 119.9 mL/m2 (112.1-127.6) vs. 79.6 mL/m2 (73.6-85.7), P<0.01]. Mean New York Heart Association class improved from 3 (2.8-3.1) to 1.8 (1.5-2) (P<0.01). The 30-day mortality was 4% (3-5%) while late mortality was 19% (9-34%) at a mean follow-up of 27.5 [21-34] months. Conclusions: In patients with ischemic cardiomyopathy, SVR reduces left ventricular volumes and improves systolic function leading to symptomatic improvement.

Reduced Recovery Times with Total Intravenous Anesthesia in Patients with Obstructive Sleep Apnea.

OBJECTIVES/HYPOTHESIS: There is currently no standard of care in terms of anesthesia modality for patients receiving upper airway surgery with comorbid obstructive sleep apnea (OSA). Although both total intravenous anesthesia (TIVA) and volatile gas anesthesia are commonly utilized in ambulatory otolaryngology surgery, it is currently unclear if there are any advantages with one modality over the other. We hypothesize that patients receiving upper airway surgery with comorbid OSA will have quicker recovery times with TIVA. STUDY DESIGN: Retrospective chart review from January 2019 to December 2019. METHODS: All patients aged 18 and older receiving upper airway surgery (upper airway stimulation, nasal surgery, modified uvulopalatopharyngoplasty) were included. Patients were excluded when there was incomplete or missing data in the electronic medical record. RESULTS: Eighty-six patients received gas anesthesia and 62 patients received TIVA. Phase I recovery times were significantly reduced by surgery and by severity of OSA: nasal surgery, upper airway stimulation, and modified uvulopalatopharyngoplasty had a reduction of 35.5 minutes (P < .001), 42.5 minutes (P < .001), and 36 minutes (P = .022), respectively. In terms of severity, mild, moderate, and severe OSA had reductions of 23.5 minutes (P = .004), 52 minutes (P = .004), and 47 minutes (P < .001), respectively. The severity of OSA generally correlated with increased time spent in Phase I: as severity increased, Phase I time increased by 16.8 minutes for the gas cohort (P < .001), whereas in the TIVA cohort, it increased only 4.3 minutes (P = .489). CONCLUSION: Patients having upper airway surgery with comorbid OSA that received TIVA (propofol and remifentanil) spent significantly less time in Phase I and the recovery room overall compared to those receiving volatile gas anesthesia in the form of sevoflurane, and this correlated with the severity of OSA. LEVEL OF EVIDENCE: 3. Laryngoscope, 131:925-931, 2021.

Glioblastoma with deep supratentorial extension is associated with a worse overall survival.

Glioblastoma (GBM) with deep-supratentorial extension (DSE) involving the thalamus, basal ganglia and corpus collosum, poses significant challenges for clinical management. In this study, we present our outcomes in patients who underwent resection of supratentorial GBM with associated involvement of deep brain structures. We conducted a retrospective review of patients who underwent resection of GBM at our institution between 2012 and 2018. A total of 419 patients were included whose pre-operative MRI scans were reviewed. Of these, 143 (34.1%) had GBM with DSE. There were similar rates of IDH-1 mutation (9% versus 7.6%, p = 0.940) and MGMT methylation status (35.7% versus 45.2%, p = 0.397) between the two cohorts. GBM patients without evidence of DSE had higher rates of radiographic gross total resection (GTR) compared to those with DSE: 70.6% versus 53.1%, respectively (p = 0.002). The presence of DSE was not associated with decreased progression-free survival (PFS) compared to patients without DSE (mean 7.24 ± 0.97 versus 8.89 ± 0.76 months, respectively; p = 0.276), but did portend a worse overall survival (OS) (mean 10.55 ± 1.04 versus 15.02 ± 1.05 months, respectively; p = 0.003). There was no difference in PFS or OS amongst DSE and non-DSE patients who underwent GTR, but patients who harbored DSE and underwent subtotal resection had worse OS (mean 8.26 ± 1.93 versus 12.96 ± 1.59 months, p = 0.03). Our study shows that GBM patients with DSE have lower OS compared to those without DSE. This survival difference appears to be primarily related to the limited surgical extent of resection owing to the neurological deficits that may be incurred with involvement of eloquent deep brain structures.

Pleiotropic Phenotypes Associated With PKP2 Variants.

Plakophilin-2 (PKP2) is a component of the desmosome complex and known for its role in cell-cell adhesion. Recently, alterations in the Pkp2 gene have been associated with different inherited cardiac conditions including Arrythmogenic Cardiomyopathy (ACM or ARVC), Brugada syndrome (BrS), and idiopathic ventricular fibrillation to name the most relevant. However, the assessment of pathogenicity regarding the genetic variations associated with Pkp2 is still a challenging task: the gene has a positive Residual Variation Intolerance Score and the potential deleterious role of several of its variants has been disputed. Limitations in facilitating interpretation and annotations of these variants are seen in the lack of segregation and clinical data in the control population of reference. In this review, we will provide a summary of all the currently available genetic information related to the Pkp2 gene, including different phenotypes, ClinVar annotations and data from large control database. Our goal is to provide a literature review that could help clinicians and geneticists in interpreting the role of Pkp2 variants in the context of heritable sudden death syndromes. Limitations of current algorithms and data repositories will be discussed.

Blockade of the Adenosine 2A Receptor Mitigates the Cardiomyopathy Induced by Loss of Plakophilin-2 Expression.

Background: Mutations in plakophilin-2 (PKP2) are the most common cause of familial Arrhythmogenic Right Ventricular Cardiomyopathy, a disease characterized by ventricular arrhythmias, sudden death, and progressive fibrofatty cardiomyopathy. The relation between loss of PKP2 expression and structural cardiomyopathy remains under study, though paracrine activation of pro-fibrotic intracellular signaling cascades is a likely event. Previous studies have indicated that ATP release into the intracellular space, and activation of adenosine receptors, can regulate fibrosis in various tissues. However, the role of this mechanism in the heart, and in the specific case of a PKP2-initiated cardiomyopathy, remains unexplored. Objectives: To investigate the role of ATP/adenosine in the progression of a PKP2-associated cardiomyopathy. Methods: HL1 cells were used to study PKP2- and Connexin43 (Cx43)-dependent ATP release. A cardiac-specific, tamoxifen-activated PKP2 knock-out murine model (PKP2cKO) was used to define the effect of adenosine receptor blockade on the progression of a PKP2-dependent cardiomyopathy. Results: HL1 cells silenced for PKP2 showed increased ATP release compared to control. Knockout of Cx43 in the same cells blunted the effect. PKP2cKO transcriptomic data revealed overexpression of genes involved in adenosine-receptor cascades. Istradefylline (an adenosine 2A receptor blocker) tempered the progression of fibrosis and mechanical failure observed in PKP2cKO mice. In contrast, PSB115, a blocker of the 2B adenosine receptor, showed opposite effects. Conclusion: Paracrine adenosine 2A receptor activation contributes to the progression of fibrosis and impaired cardiac function in animals deficient in PKP2. Given the limitations of the animal model, translation to the case of patients with PKP2 deficiency needs to be done with caution.

Modulation of Heart Rate by Acute or Chronic Aerobic Exercise. Potential Effects on Blood Pressure Control.

It was initially assumed that heart rate and arterial blood pressure were modulated by normal respiration and muscle contraction. The arterial baroreflex, an inverse relationship between blood pressure and heart rate, was later reported. Nonetheless, it was then assumed that those responses involved vagal modulation. We summarize available evidence on the modulation of heart rate by acute or chronic aerobic exercise as well as its potential implications on blood pressure (BP) control. Numerous studies have tried to clarify whether aerobic exercise modifies neurally-mediated vasoconstriction, but they report contradictory results. In view of these incongruities, the aim of this narrative review is to summarize available evidence on the modulation of heart rate by acute or chronic aerobic exercise as well as its potential implications on BP control. We mainly focus on the effects of aerobic exercise in both heart rate and blood pressure. Heart rate and heart rate variability have been indistinctly considered similar metrics, but they have completely different meanings when properly used. Both are risk markers in cardiac disease, whereas heart rate variability is also an index of sympathovagal modulation of heart rate. On the other hand, heart rate recovery has been also used as an index for mirroring both cardiovascular fitness and autonomic function, and can be used as a measure of vagal reactivation. Importantly, it is now wellknown that a reduced rate of heart rate recovery represents a powerful predictor of overall mortality. In this review, due to its complexity, we have included studies in which any of these three parameters have been analyzed.

Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm.

Plakophilin-2 (PKP2) is a component of the desmosome and known for its role in cell-cell adhesion. Mutations in human PKP2 associate with a life-threatening arrhythmogenic cardiomyopathy, often of right ventricular predominance. Here, we use a range of state-of-the-art methods and a cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout mouse to demonstrate that in addition to its role in cell adhesion, PKP2 is necessary to maintain transcription of genes that control intracellular calcium cycling. Lack of PKP2 reduces expression of Ryr2 (coding for Ryanodine Receptor 2), Ank2 (coding for Ankyrin-B), Cacna1c (coding for CaV1.2) and Trdn (coding for triadin), and protein levels of calsequestrin-2 (Casq2). These factors combined lead to disruption of intracellular calcium homeostasis and isoproterenol-induced arrhythmias that are prevented by flecainide treatment. We propose a previously unrecognized arrhythmogenic mechanism related to PKP2 expression and suggest that mutations in PKP2 in humans may cause life-threatening arrhythmias even in the absence of structural disease.It is believed that mutations in desmosomal adhesion complex protein plakophilin 2 (PKP2) cause arrhythmia due to loss of cell-cell communication. Here the authors show that PKP2 controls the expression of proteins involved in calcium cycling in adult mouse hearts, and that lack of PKP2 can cause arrhythmia in a structurally normal heart.