The Impact of Sex and Arterial Stiffness Interactions on the Outcome after an Acute Ischemic Stroke: A Retrospective Cohort Study.

Background/Objectives: Arterial stiffness (AS) is an independent predictor of cardiovascular events and is associated with a poor prognosis. While AS may represent a novel therapeutic target, recent evidence shows that it is sexually dimorphic. The aim of this study was to evaluate relative sex differences in arterial stiffness and their possible impact on the outcome of acute ischemic stroke. Methods: We retrospectively evaluated a cohort of adult patients with the following inclusion criteria: acute ischemic stroke, which occurred within 24 h from the onset of symptoms, confirmed through neuroimaging examinations, additional evaluations including extracranial and transcranial arterial ultrasound examinations, transthoracic echocardiography, a 12-lead resting ECG, and continuous 24 h in-hospital blood pressure monitoring. Based on the 24 h blood pressure monitoring, the following parameters were evaluated: systolic blood pressure, diastolic blood pressure, mean blood pressure, pulse pressure, and arterial stiffness index (ASI). The modified Rankin scale (mRS) was assessed at 90 days to evaluate the 3-month clinical outcome, defining an unfavorable outcome as an mRS score ≥ 3. To assess the factors associated with unfavorable outcomes, a stepwise logistic regression model was performed on the total sample size, and the analyses were replicated after stratifying by sex. Results: A total of 334 patients (176 males, 158 females) were included in the analysis. There was a significant sex-dependent impact of ASI on the 90-day unfavorable Rankin score (mRS score ≥ 3) as only men had a reduced likelihood of favorable outcomes with increasing arterial stiffness (OR:1.54, 95% CI: 1.06-2.23; P-interaction = 0.023). Conclusions: The influence of ASI on the 3-month functional outcome after acute ischemic stroke is at least in part sex-related, suggesting that, in males, higher ASI values are associated with a worse outcome.

Life-Threatening Arrhythmias in Patients With Takotsubo Syndrome: Insights Into Pathophysiology and Treatment Innovations.

Takotsubo syndrome (TTS) is a reversible form of acute myocardial injury due to a neurocardiogenic mechanism associated with a relevant risk for life-threatening ventricular arrhythmias, occurring in up to 25% of all patients and including both ventricular arrhythmias (especially) in the context of QT prolongation and atrial tachy- or bradyarrhythmias. The pathogenetic mechanisms of TTS-related arrhythmic complications are not completely understood, and there are no randomized clinical trials addressing the pharmacologic and nonpharmacologic management in this specific setting. In this narrative review, the authors provide an overview of the pathogenesis and the therapeutic management of arrhythmic complications in patients with TTS, along with the future perspectives and the remaining knowledge gaps in this field.

Advanced Atrioventricular Block in Athletes: Prevalence and Role of Anti-Ro/Sjögren Syndrome-Related Antigen A Antibodies.

BACKGROUND: Advanced atrioventricular block (AVB), that is, higher than second-degree Mobitz-1, is an abnormal finding in athletes. Despite intensive investigation, in several cases the pathogenesis remains unknown, but frequently pacemaker implantation is still indicated. Increasing evidence points to circulating anti-Ro/Sjögren syndrome-related antigen A (SSA) antibodies cross-reacting with L-type calcium channel and inhibiting the related current as an epidemiologically relevant and potentially reversible cause of isolated AVB in adults. The aim of the study was to determine the prevalence of anti-Ro/SSA-associated advanced AVBs in a large sample of young athletes. METHODS AND RESULTS: A total of 2536 consecutive athletes aged <40 years without a history of cardiac diseases/interventions were enrolled in a cross-sectional study. Resting and exercise electrocardiography was performed, and those presenting any AVB were further evaluated by 24-hour Holter ECG. Athletes with second-degree AVBs and their mothers underwent anti-Ro/SSA testing. Moreover, purified immunoglobulin G from subjects with anti-Ro/SSA-positive and anti-Ro/SSA-negative advanced AVB were tested on L-type calcium current and L-type-calcium channel expression using tSA201 cells. The global prevalence of advanced AVB in the overall sample was ≈0.1%, but the risk considerably increased (2%) when intensely trained postpubertal male subjects were selectively considered. While none of the athletes with advanced AVB showed heart abnormalities, in 100% of cases anti-Ro/SSA antibodies were detected. Ex vivo experiments showed that immunoglobulin G from anti-Ro/SSA-positive but not -negative subjects with advanced AVB acutely inhibit L-type calcium current and chronically downregulate L-type-calcium channel expression. CONCLUSIONS: Our study provides evidence that advanced AVB occurs in young athletes, in most cases associated with anti-Ro/SSA antibodies blocking L-type calcium channels. These findings may open new avenues for immunomodulating therapies to reduce the risk of life-threatening events in athletes, avoiding or delaying pacemaker implantation.

Elevated Interleukin-6 Levels Are Associated With an Increased Risk of QTc Interval Prolongation in a Large Cohort of US Veterans.

BACKGROUND: Although accumulating data indicate that IL-6 (interleukin-6) can promote heart rate-corrected QT interval (QTc) prolongation via direct and indirect effects on cardiac electrophysiology, current evidence comes from basic investigations and small clinical studies only. Therefore, IL-6 is still largely ignored in the clinical management of long-QT syndrome and related arrhythmias. The aim of this study was to estimate the risk of QTc prolongation associated with elevated IL-6 levels in a large population of unselected subjects. METHODS AND RESULTS: An observational study using the Veterans Affairs Informatics and Computing Infrastructure was performed. Participants were US veterans who had an ECG and were tested for IL-6. Descriptive statistics and univariate and multivariate regression analyses were performed to study the relationship between IL-6 and QTc prolongation risk. Study population comprised 1085 individuals, 306 showing normal (<5 pg/mL), 376 moderately high (5-25 pg/mL), and 403 high (>25 pg/mL) IL-6 levels. Subjects with elevated IL-6 showed a concentration-dependent increase in the prevalence of QTc prolongation, and those presenting with QTc prolongation exhibited higher circulating IL-6 levels. Stepwise multivariate regression analyses demonstrated that increased IL-6 level was significantly associated with a risk of QTc prolongation up to 2 times the odds of the reference category of QTc (e.g. QTc >470 ms men/480 ms women ms: odds ratio, 2.28 [95% CI, 1.12-4.50] for IL-6 >25 pg/mL) regardless of the underlying cause. Specifically, the mean QTc increase observed in the presence of elevated IL-6 was quantitatively comparable (IL-6 >25 pg/mL:+6.7 ms) to that of major recognized QT-prolonging risk factors, such as hypokalemia and history of myocardial infarction. CONCLUSIONS: Our data provide evidence that a high circulating IL-6 level is a robust risk factor for QTc prolongation in a large cohort of US veterans, supporting a potentially important arrhythmogenic role for this cytokine in the general population.

Pathogenic pathways and therapeutic targets of inflammation in heart diseases: A focus on Interleukin-1.

BACKGROUND: An exuberant and dysregulated inflammatory response contributes to the development and progression of cardiovascular diseases (CVDs). METHODS: This narrative review includes original articles and reviews published over the past 20 years and found through PubMed. The following search terms (or combination of terms) were considered: "acute pericarditis," "recurrent pericarditis," "myocarditis," "cardiac sarcoidosis," "atherosclerosis," "acute myocardial infarction," "inflammation," "NLRP3 inflammasome," "Interleukin-1" and "treatment." RESULTS: Recent evidence supports the role of inflammation across a wide spectrum of CVDs including myocarditis, pericarditis, inflammatory cardiomyopathies (i.e. cardiac sarcoidosis) as well as atherosclerotic CVD and heart failure. Interleukins (ILs) are the signalling mediators of the inflammatory response. The NACHT, leucine-rich repeat and pyrin-domain containing protein 3 (NLRP3) inflammasome play a key role in producing IL-1ß, the prototypical pro-inflammatory cytokine involved in CVDs. Other pro-inflammatory cytokines (e.g. tumour necrosis factor) have been implicated in cardiac sarcoidosis. As a proof of this, IL-1 blockade has been proven efficacious in pericarditis and chronic coronary syndrome. CONCLUSION: Tailored strategies aiming at quenching the inflammatory response have emerged as promising to treat CVDs. In this review article, we summarize recent evidence regarding the role of inflammation across a broad spectrum of CVDs. We also review novel evidence regarding targeted therapeutic strategies.

Fir(e)ing the Rhythm: Inflammatory Cytokines and Cardiac Arrhythmias.

Inflammatory activation is increasingly recognized as a nonconventional risk factor for arrhythmias, and experimental studies provided robust evidence that this association is mediated by direct arrhythmogenic effects of proinflammatory cytokines on cardiac cells. Additionally, inflammatory cytokines can favor arrhythmias indirectly through multiple systemic effects. Accumulating data confirm the clinical relevance of these mechanisms; the largest evidence being available for atrial fibrillation, acquired long-QT syndrome, and ventricular arrhythmias. However, clinical management of arrhythmias largely neglects inflammatory cytokines. This review integrates basic science and clinical research to present an updated overview of the topic and provides future directions for patient's management.

Anti-Ro/SSA Antibodies Blocking Calcium Channels as a Potentially Reversible Cause of Atrioventricular Block in Adults.

BACKGROUND: In ∼50% of severe atrioventricular blocks (AVBs) occurring in adults <50 years, the underlying etiology remains unknown. Preliminary evidence from case reports suggests that autoimmunity, specifically the presence of circulating anti-Ro/SSA antibodies in the patient (acquired form), in the patient's mother (late-progressive congenital form), or in both (mixed form), could be involved in a fraction of idiopathic AVBs in adults by possibly targeting the L-type calcium channel (Cav1.2) and inhibiting the related current (ICaL). OBJECTIVES: The purpose of this study was to evaluate whether anti-Ro/SSA antibodies are causally implicated in the development of isolated AVBs in adults. METHODS: Thirty-four consecutive patients with isolated AVB of unknown origin and 17 available mothers were prospectively enrolled in a cross-sectional study. Anti-Ro/SSA antibodies were assessed by fluoroenzyme-immunoassay, immuno-Western blotting, and line-blot immunoassay. Purified immunoglobulin-G (IgG) from anti-Ro/SSA-positive and anti-Ro/SSA-negative subjects were tested on ICaL and Cav1.2 expression using tSA201 and HEK293 cells, respectively. Moreover, in 13 AVB patients, the impact of a short course of steroid therapy on AV conduction was evaluated. RESULTS: Anti-Ro/SSA antibodies, particularly anti-Ro/SSA-52kD, were found in 53% of AVB-patients and/or in their mothers, most commonly an acquired or mixed form (two-thirds of cases) without history of autoimmune diseases. Purified IgG from anti-Ro/SSA-positive but not anti-Ro/SSA-negative AVB patients acutely inhibited ICaL and chronically down-regulated Cav1.2 expression. Moreover, anti-Ro/SSA-positive sera showed high reactivity with peptides corresponding to the Cav1.2 channel pore-forming region. Finally, steroid therapy rapidly improved AV conduction in AVB-patients with circulating anti-Ro/SSA antibodies but not in those without. CONCLUSIONS: Our study points to anti-Ro/SSA antibodies as a novel, epidemiologically relevant and potentially reversible cause of isolated AVB in adults, via an autoimmune-mediated functional interference with the L-type calcium channels. These findings have significant impact on antiarrhythmic therapies by avoiding or delaying pacemaker implantation.

Cryptogenic stroke as a working diagnosis: the need for an early and comprehensive diagnostic work-up.

In the Nordic Atrial Fibrillation and Stroke (NOR-FIB) study, the causes of ischemic stroke were identified in 43% of cryptogenic stroke patients monitored with implantable cardiac monitor (ICM), but one-third of these patients had non-cardioembolic causes. These results suggest the need for an early and comprehensive diagnostic work-up before inserting an ICM.

Contribution of cytokine-mediated prolongation of QTc interval to the multi-hit theory of Torsade de Pointes.

BACKGROUND: Torsade de pointes is a potentially lethal polymorphic ventricular tachyarrhythmia that can occur in the setting of long QT syndrome (LQTS). LQTS is multi-hit in nature and multiple factors combine their effects leading to increased arrhythmic risk. While hypokalemia and multiple medications are accounted for in LQTS, the arrhythmogenic role of systemic inflammation is increasingly recognized but often overlooked. We tested the hypothesis that the inflammatory cytokine interleukin(IL)-6 will significantly increase the incidence of arrhythmia when combined with other pro-arrhythmic conditions (hypokalemia and the psychotropic medication, quetiapine). METHODS: Guinea pigs were injected intraperitoneally with IL-6/soluble IL-6 receptor and QT changes were measured in vivo. Subsequently, hearts were cannulated via Langendorff perfusion for ex vivo optical mapping measurements of action potential duration (APD90) and arrhythmia inducibility. Computer simulations (MATLAB) were performed to investigate IKr inhibition at varying IL-6 and quetiapine concentrations. RESULTS: IL-6 prolonged QTc in vivo guinea pigs from 306.74 ± 7.19 ms to 332.60 ± 8.75 ms (n = 8, p = .0021). Optical mapping on isolated hearts demonstrated APD prolongation in IL-6- vs saline groups (3Hz APD90:179.67 ± 2.47 ms vs 153.5 ± 7.86 ms, p = .0357). When hypokalemia was introduced, the APD90 increased to 195.8 ± 5.02 ms[IL-6] and 174.57 ± 10.7 ms[saline] (p = .2797), and when quetiapine was added to hypokalemia to 207.67 ± 3.03 ms[IL-6] and 191.37 ± 9.49 ms[saline] (p = .2449). After the addition of hypokalemia ± quetiapine, arrhythmia was induced in 75% of IL-6-treated hearts (n = 8), while in none of the control hearts (n = 6). Computer simulations demonstrated spontaneous depolarizations at ∼83% aggregate IKr inhibition. CONCLUSIONS: Our experimental observations strongly suggest that controlling inflammation, specifically IL-6, could be a viable and important route for reducing QT prolongation and arrhythmia incidence in the clinical setting.

Maternal Anti-Ro/SSA Autoantibodies and Prolonged PR Interval in a Competitive Athlete: Beyond Training-Induced Electrical Remodeling.

Prolongation of the PR interval is common among competitive athletes. However, further investigations should be performed when the PR interval is markedly prolonged. We report the case of a young male athlete with an autoimmune-mediated atrioventricular block due to circulating anti-Ro/SSA-antibodies in the mother (late progressive congenital form). (Level of Difficulty: Advanced.).

Markers of Atrial Cardiopathy in Severe Embolic Strokes of Undetermined Source.

Background and Purpose: The current definition of embolic strokes of undetermined source (ESUS) seems to be too broad, including strokes due to heterogeneous mechanisms, such as atrial cardiopathy and other occult cardiac conditions, aortic arch plaques, and non-stenosing atherosclerosis, that can be differently associated with clinical stroke severity at the time of presentation. The aim of our study was to assess the possible association between neurological deficit severity and presence of markers of atrial cardiopathy in ESUS. Methods: We retrospectively reviewed the medical records of a cohort of 226 ESUS patients (105 M, 121 F), that were divided into two groups according to the severity of neurological deficit (99 mild strokes with NIHSS ≤ 5 and 127 severe strokes with NIHSS >5). The following indices of atrial cardiopathy were evaluated: P wave dispersion, P wave max, P wave min, P wave mean, P wave index, P wave axis, left atrial size. Results: Patients with severe ESUS were significantly older (74 ± 12 vs. 67 ± 14 years, P < 0.001) and female sex was prevalent (67 vs. 36%, P > 0.001); they had higher values of P-wave-dispersion (51 ± 14 vs. 46 ± 13, P = 0.01), P-wave-max (131 ± 20 vs. 125 ± 15 ms, P = 0.01), P-wave-index (16 ± 5 vs. 15 ± 5 ms, P = 0.01), left atrial size (20 ± 6 vs. 18 ± 4 cm2, P = 0.01), left atrial volume index (31 ± 14 vs. 27 ± 11 ml/m2, P = 0.04), in comparison with mild ESUS. An abnormal P wave axis was detected more frequently in severe ESUS (21 vs. 9%, P = 0.01). Furthermore, multivariate logistic regression showed that age (OR = 1.21 for each 5-year increase, 95% CI 1.09-1.35), sex (OR = 3.24 for female sex, 95% CI 1.82-5.76) and PWD (OR = 1.32 for each 10-ms increase, 95% CI 1.07-1.64) were the best subset of associated variables for severe ESUS. Conclusions: Our findings shed light on specific clinical characteristics of severe ESUS including the presence of atrial cardiopathy that could play a pathogenic role in this subgroup of patients. Searching for atrial fibrillation in these patients is especially important to perform the most appropriate therapy.