Atrial fibrillation burden: Stepping beyond the categorical characterization.

Traditional classifications categorize atrial fibrillation (AF) into paroxysmal, persistent or permanent, but recent advancements in monitoring have revealed AF as a continuous variable, challenging existing paradigms. AF burden, defined basically as the amount of time spent in AF during a monitored period, has emerged as a crucial metric. This review assesses the evolving landscape of AF burden and its measurement methods, diagnostic modalities, and impact on outcomes. Guidelines suggest individualized approaches, combining AF burden with clinical scores (CHA2DS2-VASc), but recent studies have challenged this. Addressing the impact of AF burden on patients' quality of life before or after ablation is also crucial. Although continuous monitoring technologies offer promising avenues, the field faces challenges such as defining clinically relevant thresholds. Future research should focus on refining these, designing trials centered around AF burden, and evaluating the efficacy of interventions in reducing AF burden, ultimately paving the way for personalized management strategies.

Differential Mitochondrial Bioenergetics in Neurons and Astrocytes Following Ischemia-Reperfusion Injury and Hypothermia.

The close interaction between neurons and astrocytes has been extensively studied. However, the specific behavior of these cells after ischemia-reperfusion injury and hypothermia remains poorly characterized. A growing body of evidence suggests that mitochondria function and putative transference between neurons and astrocytes may play a fundamental role in adaptive and homeostatic responses after systemic insults such as cardiac arrest, which highlights the importance of a better understanding of how neurons and astrocytes behave individually in these settings. Brain injury is one of the most important challenges in post-cardiac arrest syndrome, and therapeutic hypothermia remains the single, gold standard treatment for neuroprotection after cardiac arrest. In our study, we modeled ischemia-reperfusion injury by using in vitro enhanced oxygen-glucose deprivation and reperfusion (eOGD-R) and subsequent hypothermia (HPT) (31.5 °C) to cell lines of neurons (HT-22) and astrocytes (C8-D1A) with/without hypothermia. Using cell lysis (LDH; lactate dehydrogenase) as a measure of membrane integrity and cell viability, we found that neurons were more susceptible to eOGD-R when compared with astrocytes. However, they benefited significantly from HPT, while the HPT effect after eOGD-R on astrocytes was negligible. Similarly, eOGD-R caused a more significant reduction in adenosine triphosphate (ATP) in neurons than astrocytes, and the ATP-enhancing effects from HPT were more prominent in neurons than astrocytes. In both neurons and astrocytes, measurement of reactive oxygen species (ROS) revealed higher ROS output following eOGD-R, with a non-significant trend of differential reduction observed in neurons. HPT after eOGD-R effectively downregulated ROS in both cells; however, the effect was significantly more effective in neurons. Lipid peroxidation was higher after eOGD-R in neurons, while in astrocytes, the increase was not statistically significant. Interestingly, HPT had similar effects on the reduction in lipoperoxidation after eOGD-R with both types of cells. While glutathione (GSH) levels were downregulated after eOGD-R in both cells, HPT enhanced GSH in astrocytes, but worsened GSH in neurons. In conclusion, neuron and astrocyte cultures respond differently to eOGD-R and eOGD-R + HTP treatments. Neurons showed higher sensitivity to ischemia-reperfusion insults than astrocytes; however, they benefited more from HPT therapy. These data suggest that given the differential effects from HPT in neurons and astrocytes, future therapeutic developments could potentially enhance HPT outcomes by means of neuronal and astrocytic targeted therapies.

Cardioneuroablation for Drug Refractory Vasovagal Syncope After COVID-19 Infection.

Cardioneuroablation is a novel approach to treat patients with recurrent vasovagal syncope (VVS), targeting the ganglionated plexi around the atria and thus reducing the vagal input to the heart. This study reports a case of drug-refractory VVS after COVID-19 infection, successfully managed with cardioneuroablation.

Rhythm vs Rate Control Strategy for Atrial Fibrillation: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Rhythm control, either with antiarrhythmic drugs or catheter ablation, and rate control strategies are the cornerstones of atrial fibrillation (AF) management. Despite the increasing role of rhythm control over the past few years, it remains inconclusive which strategy is superior in improving clinical outcomes. OBJECTIVES: This study summarizes the total and time-varying evidence regarding the efficacy of rhythm- vs rate-control strategies in the management of AF. METHODS: We systematically perused the MEDLINE, CENTRAL (Cochrane Central Register of Controlled Trials), and Web of Science databases for randomized controlled trials from inception to November 2023. We included studies that compared the efficacy of rhythm control (ie, antiarrhythmic drugs classes Ia, Ic, or III, AF catheter ablation, and electrical cardioversion) and rate control (ie, beta-blocker, digitalis, or calcium antagonist) strategies among patients with nonvalvular AF. The primary outcome was cardiovascular (CV) death, whereas secondary outcomes included all-cause death, stroke, hospitalization for heart failure (HF), sinus rhythm at the end of the follow-up, and rhythm control-related adverse events. A cumulative meta-analysis to assess temporal trends and a meta-regression analysis using the percentage of ablation use was performed. RESULTS: We identified 18 studies with a total of 17,536 patients (mean age: 68.6 ± 9.7 years, 37.9% females) and a mean follow-up of 28.5 months. Of those, 31.9% had paroxysmal AF. A rhythm control strategy reduced CV death (HR: 0.78; 95% CI: 0.62-0.96), stroke (HR: 0.801; 95% CI: 0.643-0.998), and hospitalization for HF (HR: 0.80; 95% CI: 0.69-0.94) but not all-cause death (HR: 0.86; 95% CI: 0.73-1.02) compared with a rate control strategy. This benefit was driven by contemporary studies, whereas more ablation use within the rhythm control arm was associated with improved outcomes, except stroke. CONCLUSIONS: In patients with AF, a contemporary rhythm control strategy leads to reduced CV mortality, HF events, and stroke compared with a rate control strategy.

Ultrasound Neuromodulation of an Anti-Inflammatory Pathway at the Spleen Improves Experimental Pulmonary Hypertension.

BACKGROUND: Inflammation is pathogenically implicated in pulmonary arterial hypertension; however, it has not been adequately targeted therapeutically. We investigated whether neuromodulation of an anti-inflammatory neuroimmune pathway involving the splenic nerve using noninvasive, focused ultrasound stimulation of the spleen (sFUS) can improve experimental pulmonary hypertension. METHODS: Pulmonary hypertension was induced in rats either by Sugen 5416 (20 mg/kg SQ) injection, followed by 21 (or 35) days of hypoxia (sugen/hypoxia model), or by monocrotaline (60 mg/kg IP) injection (monocrotaline model). Animals were randomized to receive either 12-minute-long sessions of sFUS daily or sham stimulation for 14 days. Catheterizations, echocardiography, indices of autonomic function, lung and heart histology and immunohistochemistry, spleen flow cytometry, and lung single-cell RNA sequencing were performed after treatment to assess the effects of sFUS. RESULTS: Splenic denervation right before induction of pulmonary hypertension results in a more severe disease phenotype. In both sugen/hypoxia and monocrotaline models, sFUS treatment reduces right ventricular systolic pressure by 25% to 30% compared with sham treatment, without affecting systemic pressure, and improves right ventricular function and autonomic indices. sFUS reduces wall thickness, apoptosis, and proliferation in small pulmonary arterioles, suppresses CD3+ and CD68+ cell infiltration in lungs and right ventricular fibrosis and hypertrophy and lowers BNP (brain natriuretic peptide). Beneficial effects persist for weeks after sFUS discontinuation and are more robust with early and longer treatment. Splenic denervation abolishes sFUS therapeutic benefits. sFUS partially normalizes CD68+ and CD8+ T-cell counts in the spleen and downregulates several inflammatory genes and pathways in nonclassical and classical monocytes and macrophages in the lung. Differentially expressed genes in those cell types are significantly enriched for human pulmonary arterial hypertension-associated genes. CONCLUSIONS: sFUS causes dose-dependent, sustained improvement of hemodynamic, autonomic, laboratory, and pathological manifestations in 2 models of experimental pulmonary hypertension. Mechanistically, sFUS normalizes immune cell populations in the spleen and downregulates inflammatory genes and pathways in the lung, many of which are relevant in human disease.

Catheter ablation as an adjunctive therapy to ICD implantation in Brugada syndrome.

BACKGROUND: Brugada Syndrome (BrS) is a life-threatening cardiac arrhythmia disorder associated with an increased risk ventricular arrhythmias (VAs) and sudden cardiac death (SCD). Current management primarily relies on implantable cardioverter-defibrillators (ICDs), but patients may experience ICD shocks. Catheter ablation (CA) has emerged as a potential intervention to target the arrhythmogenic substrate. This systematic review aims to evaluate the safety and efficacy of catheter ablation in BrS patients. METHODS AND RESULTS: Studies with BrS patients undergoing catheter ablation for VAs were included. 14 studies that involved a total population of 709 BrS patients, with catheter ablation performed in 528 of them, were included. Catheter ablation resulted in non-inducibility of VAs in 91% (95% CI: 83-99, I2 = 76%) and resolution of Type 1 ECG Brugada pattern in 88% (95% CI: 81-96.2, I2 = 91%) of the patients. After a mean follow-up of 30.7 months, 87% (95% CI: 80-94, I2 = 82%) of patients remained free from VAs. The incidence of VAs during follow-up was significantly lower in the ablation cohort in comparison to the group receiving only ICD therapy (OR = 0.03, 95% CI: 0.01-0.12, I2 = 0%). CONCLUSION: Catheter ablation shows potential as a therapeutic approach to reduce VAs and improve outcomes in BrS patients. While further research with long follow-up period is required to confirm these findings, it represents a valuable tool as an add-on intervention to ICD implantation in BrS patients with high burden of VAs.Protocol registration: CRD42024506439.

Contribution of pressure and flow changes to resistance reduction after pulmonary arterial hypertension treatment: a meta-analysis of 3898 patients.

Background: Pulmonary arterial hypertension (PAH)-targeted therapies exert significant haemodynamic changes; however, systematic synthesis is currently lacking. Methods: We searched PubMed, CENTRAL and Web of Science for studies evaluating mean pulmonary artery pressure (mPAP), cardiac index/cardiac output (CI/CO) and pulmonary vascular resistance (PVR) of PAH-targeted therapies either in monotherapy or combinations as assessed by right heart catheterisation in treatment-naïve PAH patients. We performed a random-effects meta-analysis with meta-regression. Results: We included 68 studies (90 treatment groups) with 3898 patients (age 47.4±13.2 years, 74% women). In studies with small PVR reduction (<4 WU), CI/CO increase (R2=62%) and not mPAP reduction (R2=24%) was decisive for the PVR reduction (p<0.001 and p=0.36, respectively, in the multivariable meta-regression model); however, in studies with large PVR reduction (>4 WU), both CI/CO increase (R2=72%) and mPAP reduction (R2=35%) contributed significantly to the PVR reduction (p<0.001 and p=0.01, respectively). PVR reduction as a percentage of the pre-treatment value was more pronounced in the oral+prostanoid intravenous/subcutaneous combination therapy (mean difference -50.0%, 95% CI -60.8- -39.2%), compared to oral combination therapy (-41.7%, -47.6- -35.8%), prostanoid i.v./s.c. monotherapy (-31.8%, -37.6- -25.9%) and oral monotherapy (-21.6%, -25.4- -17.8%). Changes in haemodynamic parameters were significantly associated with changes in functional capacity of patients with PAH as expressed by the 6-min walking distance. Conclusion: Combination therapies, especially with the inclusion of parenteral prostanoids, lead to remarkable haemodynamic improvement in treatment-naïve PAH patients and may unmask the contribution of mPAP reduction to the overall PVR reduction in addition to the increase in CO.

Pharmacological Treatments in Heart Failure With Mildly Reduced and Preserved Ejection Fraction: Systematic Review and Network Meta-Analysis.

BACKGROUND: Medical treatment for heart failure with preserved ejection (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF) has weaker evidence compared with reduced ejection fraction, despite recent trials with an angiotensin receptor neprilysin inhibitor (ARNI) and sodium glucose co-transporter 2 inhibitors (SGLT2is). OBJECTIVES: The authors aimed to estimate the aggregate therapeutic benefit of drugs for HFmrEF and HFpEF. METHODS: The authors performed a systematic review of MEDLINE, CENTRAL, and Web of Science for randomized trials including patients with heart failure (HF) and left ventricular ejection fraction (LVEF) >40%, treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (analyzed together as renin-angiotensin system inhibitors [RASi]), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), digoxin, ARNI, and SGLT2i. An additive component network meta-analysis was performed. The primary outcome was a composite of cardiovascular (CV) death and first hospitalization for heart failure (HHF); secondary outcomes were CV death, total HHF, and all-cause mortality. RESULTS: The authors identified 13 studies with a total of 29,875 patients and a mean LVEF of 56.3% ± 8.7%. ARNI, MRA, and SGLT2i separately, but not RASi, BB, or digoxin, reduced the primary composite outcome compared with placebo. The combination of ARNI, BB, MRA, and SGLT2i was the most effective (HR: 0.47 [95% CI: 0.31-0.70]); this was largely explained by the triple combination of ARNI, MRA, and SGLT2i (HR: 0.56 [95% CI 0.43-0.71]). Results were similar for CV death (HR: 0.63 [95% CI 0.43-0.91] for ARNI, MRA, and SGLT2i) or total HHF (HR: 0.49 [95% CI 0.33-0.71] for ARNI, MRA, and SGLT2i) alone. In a subgroup analysis, only SGLT2i had a consistent benefit among all LVEF subgroups, whereas the triple combination had the greatest benefit in HFmrEF, robust benefit in patients with LVEF 50% to 59%, and a statistically marginal benefit in patients with LVEF ≥60%. CONCLUSIONS: In patients with HF and LVEF>40%, the quadruple combination of ARNI, BB, MRA, and SGLT2i provides the largest reduction in the risk of CV death and HHF; driven by the robust effect of the triple combination of ARNI, MRA, and SGLT2i. The benefit was more pronounced in HFmrEF patients.

COVID-19-Associated Portal Vein Thrombosis Post-Cholecystitis.

This case study describes a 45-year-old Caucasian male with a past medical history of obesity, hypertension, and non-insulin-dependent diabetes mellitus, who in the setting of coronavirus disease 2019 (COVID-19) pneumonia, developed portal vein thrombosis (PVT) presenting as an acute abdomen after hospital discharge from a cholecystitis episode. PVT is a very infrequent thromboembolic condition, classically occurring in patients with systemic conditions such as cirrhosis, malignancy, pancreatitis, diverticulitis, autoimmunity, and thrombophilia. PVT can cause serious complications, such as intestinal infarction, or even death, if not promptly treated. Due to the limited number of reports in the literature describing PVT in the COVID-19 setting, its prevalence, natural history, mechanism, and precise clinical features remain unknown. Therefore, clinical suspicion should be high for PVT, in any COVID-19 patient who presents with abdominal pain or associated signs and symptoms. To the best of our knowledge, this is the first report of COVID-19-associated PVT causing extensive thrombosis in the portal vein and its right branch, occurring in the setting of early-stage cirrhosis after a preceding episode of cholecystitis.

Effects of dietary interventions on cardiovascular outcomes: a network meta-analysis.

CONTEXT: Next to a large body of epidemiological observational studies showing that the Mediterranean diet (MD) is an important lifestyle determinant of cardiovascular risk, there is less relevant evidence from well-conducted randomized controlled trials (RCTs) with hard cardiovascular outcomes. OBJECTIVE: The objective of the study was to identify the most effective dietary intervention for reducing cardiovascular morbidity and mortality. DATA SOURCES: A systematic approach following PRISMA network meta-analyses reporting guidelines was applied to a search of electronic databases (MEDLINE, Cochrane Central Register of Controlled Trials, and Embase) without language restrictions, supplemented by scanning through bibliographies of studies and meetings' abstract material. Inclusion criteria were RCTs conducted in an adult population, investigating the effects of different type of diets or dietary patterns on all-cause mortality and cardiovascular outcomes of interest. DATA EXTRACTION: Data extraction for each study was conducted by 2 independent reviewers. DATA ANALYSIS: A frequentist network meta-analysis using a random-effects model was conducted. Death from any cardiovascular cause was defined as the primary outcome. A total of 17 trials incorporating 83 280 participants were included in the systematic review. Twelve articles (n = 80 550 participants) contributed to the network meta-analysis for the primary outcome. When compared with the control diet, only the MD showed a reduction in cardiovascular deaths (risk ratio = 0.59; 95% confidence interval, 0.42-0.82). Additionally, MD was the sole dietary strategy that decreased the risk of major cardiovascular events, myocardial infarction, angina, and all-cause mortality. CONCLUSIONS: MD may play a protective role against cardiovascular disease and death for primary and also secondary prevention. SYSTEMATIC REVIEW REGISTRATION: Center for Open Science, https://doi.org/10.17605/OSF.IO/5KX83.

Total Atrial Conduction Time as a Predictor of Atrial Fibrillation Recurrence: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis aims to evaluate the predictive value of total atrial conduction time (TACT) assessed by tissue Doppler echocardiography (PA-TDI) in atrial fibrillation (AF) recurrence in patients following a rhythm-control strategy. A systematic approach following Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines was applied in electronic databases (Pubmed, Cochrane Library, and Web of Science), supplemented by scanning through studies' references. TACT was compared using a random-effects model and presented as a difference in means (MD). The primary endpoint was AF recurrence. Seven publications were included in this systematic review. The mean age of the patients ranged from 55 years to 72 years. Prolonged TACT was associated with AF recurrence [MD, 23.12 msec; 95% confidence interval (CI), 11.54-34.71; I2 = 95%]. Subgroup analysis showed that prolonged TACT was strongly associated with AF recurrence in persistent AF cohorts undergoing electrical cardioversion (MD, 26.56; 95% CI, 15.51-37.6; I2 = 86%), while in patients with paroxysmal AF (PAF) undergoing catheter ablation, the results were not statistically significant (MD, 11.48; 95% CI, -1.19 to 24.14; I2 = 90%). The summary area under the curve (sAUC) using a random-effects model was 0.89 (95% CI, 0.80-0.99). TACT is a valuable echocardiographic parameter that can predict AF recurrence in patients following a rhythm-control strategy. Protocol registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022353018.

Vagus nerve stimulation for cardiovascular diseases: Is there light at the end of the tunnel?

Autonomic dysfunction and chronic inflammation contribute to the pathogenesis and progression of several cardiovascular diseases (CVD), such as heart failure with preserved ejection fraction, atherosclerotic CVD, pulmonary arterial hypertension, and atrial fibrillation. The vagus nerve provides parasympathetic innervation to the heart, vessels, and lungs, and is also implicated in the neural control of inflammation through a neuroimmune pathway involving the spleen. Stimulation of the vagus nerve (VNS) can in principle restore autonomic balance and suppress inflammation, with potential therapeutic benefits in these diseases. Although VNS ameliorated CVD in several animal models, early human studies have demonstrated variable efficacy. The purpose of this review is to discuss the rationale behind the use of VNS in the treatment of CVD, to critically review animal and human studies of VNS in CVD, and to propose possible means to overcome the challenges in the clinical translation of VNS in CVD.

External Stenting (Exostenting) to Correct Vascular Torsion and Angulation.

Organ transplantation can be associated with vascular torsions and angulations of both recipient and donor vessels. Such kinks and/or torsions of vessels can compromise the vascular integrity, obstruct inflow and/or outflow, and result in loss of the organ and/or body parts. On many occasions, mild angulations and torsions can be successfully addressed by repositioning the organ. In cases where the abnormal findings persist, maneuvers such as placing a fat pad to create a smoother curve, or even opening the peritoneum (in the case of kidney transplants) to allow for a better positioning of the organ, are associated with successful outcomes. When such torsions/angulations persist despite these approaches, further innovative tactics are required. In the current report, we propose a technique that involves longitudinally opening of a synthetic graft that is rigid enough to maintain its shape, such as a ringed polytetrafluoroethylene graft, and placing it as an external stent around the angulated/torsioned vessel. This maneuver will correct the underlying vascular compromise without having to perform any further invasive interventions, such as reimplanting the organ or resecting part of the involved vessel. Although primarily illustrated for application by describing an instance in which exostenting was applied during kidney transplantation, our approach could be applied to any vessel under many circumstances where angulations/twists are encountered. In this report, we describe the use of an external stent, also called exostenting, to correct a severe torsion/angulation of the external iliac artery in a kidney transplant recipient where all other measures were unsuccessful.

Effect of Parathyroidectomy on Left Ventricular Mass Index in Patients With Primary Hyperparathyroidism.

Aim Primary hyperthyroidism (PHPT) is known to affect left ventricular structure and function and may contribute to increased cardiovascular morbidity and mortality. Whether parathyroidectomy (PTX) reverses left ventricular hypertrophy/remodeling among PHPT patients remains controversial. Method In this prospective, single-center study, we enrolled patients with the diagnosis of PHPT who were scheduled for PTX. Patients underwent a complete biochemical workup and an echocardiographic examination at baseline and a six-month follow-up. The primary objective was to compare the left ventricular mass index (LVMI) at baseline and six-month follow-up. Result Eighteen patients (15 female, three male, mean age 58.7 years) were enrolled. PTH and serum calcium returned to normal immediately post-PTX and remained normal at six months. LVMI at baseline was within normal limits and reduced further at the six-month follow-up. The left ventricular ejection fraction was in the normal range before the PTX and remained unchanged during follow-up. Conclusion Curative PTX reduced LVMI further within the normal range at six months in patients with asymptomatic hyperparathyroidism, providing evidence for benefit in an important non-traditional disease manifestation.

Haemodynamic effects of initial combination therapy in pulmonary arterial hypertension: a systematic review and meta-analysis.

Background: Although the initial use of combination treatment has been proven to be beneficial for patients' clinical outcomes, there are scarce data on its haemodynamic effects. The objective of the present study was to evaluate the effect of an initial combination of pulmonary arterial hypertension (PAH)-targeted therapies on haemodynamic parameters in treatment-naïve PAH patients. Methods: A systematic search of PubMed, Cochrane Central Register of Controlled Trials and Web of Science was performed. We considered eligible studies with an intervention of initial PAH-targeted combination therapy in treatment-naïve PAH patients with or without monotherapy control. A random-effects meta-analysis was performed for the difference between baseline and follow-up in pulmonary vascular resistance (PVR) and other haemodynamic parameters. Results: In 880 patients receiving initial combination therapy PVR was reduced by -6.5 Wood Units (95% CI -7.4--5.7 Wood Units) or by -52% (95% CI -56%--48%, I2=0%) compared to baseline. Initial triple therapy including a parenteral prostanoid resulted in significantly greater PVR reduction (-67% versus -50% with all other combination therapies, p=0.01). The effect was more pronounced in younger patients (p=0.02). Compared to baseline, there was -12.2 mmHg (95% CI -14.0--10.4 mmHg) decrease in mean pulmonary artery pressure, 0.9 L·min-1·m-2 (95% CI 0.8-1.1 L·min-1·m-2) increase in cardiac index, -3.2 mmHg (95% CI -4.1--2.3 mmHg) decrease in right atrial pressure and 8.6% (95% CI 6.9-10.3%) increase in mixed venous oxygen saturation. In the controlled studies, initial combination therapy reduced PVR by -4.2 Wood Units (95% CI -6.1--2.4 Wood Units) compared to monotherapy. Conclusion: Initial combination therapy leads to remarkable haemodynamic amelioration. Parenteral prostanoids should be considered early, especially in more severely affected patients, to enable right ventricular reverse remodelling.