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A 63-year-old female with mixed connective tissue disease on long-term immunosuppression (prednisone, azathioprine, hydroxychloroquine (HCQ)) was referred to a tertiary care center for evaluation of progressive dyspnea and exertional chest discomfort. Cardiac history included transient complete heart block and ventricular tachycardia with dual-chamber AICD, and severe aortic stenosis with bicuspid aortic valve. Laboratory evaluation was notable for NT pro-BNP > 5000 pg/mL and elevated but adynamic troponin (300-500 ng/L). Electrocardiogram revealed atrial pacing with first degree atrioventricular block. Echocardiogram confirmed severe aortic stenosis, elevated filling pressures, abnormal left ventricular longitudinal strain and LV hypertrophy. Cardiac MRI, sarcoid PET, and PYP SPECT/CT were without any evidence of edema, scar, inflammation or amyloid deposition. Catheterization revealed severe pulmonary hypertension and elevated filling pressures, without significant coronary disease. Medical treatment included empagliflozin (discontinued due to urosepsis), bumetanide, spironolactone, and metoprolol succinate. Neither TAVR nor transition to biventricular pacing improved LV function. Ultimately, endomyocardial biopsy was performed, revealing histologic features of HCQ-induced cardiotoxicity, including myocyte hypertrophy and interstitial fibrosis. HCQ was discontinued. She was referred to Rheumatology for alternative treatments. HCQ induced cardiomyopathy represents <2% of adverse events of patients treated with HCQ, presenting as hypertrophic or restrictive cardiomyopathy with conduction abnormalities. Mean treatment duration in HCQ cardiomyopathies is approximately 12.7 years. Confirmation of diagnosis requires endomyocardial biopsy, as imaging findings are often non-specific. Management involves discontinuing the offending agent and optimizing heart failure therapy. Around 45% of patients with HCQ cardiomyopathy exhibit resolution of cardiac function following medication discontinuation. This case emphasizes the importance of a systematic approach to unexplained heart failure, particularly in patients with long-term HCQ use. Infiltrative or toxic cardiomyopathies should be considered when imaging suggests myocardial dysfunction. Multimodal imaging and biopsy are crucial for diagnosis. Early recognition is essential to prevent irreversible myocardial damage and improve long-term outcomes.

Background: Chronic right ventricular pacing (RVP) can lead to electrical dyssynchrony, often resulting in pacemaker-induced cardiomyopathy (PICM). Although biventricular pacing (BiVP) is a standard upgrade strategy, it is associated with notable rates of non-response and procedural limitations. Conduction system pacing (CSP), including His bundle pacing (HBP) and left bundle branch pacing (LBBP), offers a more physiological approach by directly engaging the native conduction system. Emerging evidence supports the role of His-Purkinje conduction system pacing (HPCSP) in reversing adverse remodeling and improving clinical outcomes in PICM patients. Methods: A comprehensive literature search was performed across PubMed, Embase, Cochrane Library, and ClinicalTrials.gov through January 2025. Studies were included if they evaluated outcomes in patients with PICM who had been chronically paced in the right ventricle and subsequently upgraded to HPCSP. Key endpoints included changes in left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) functional class. Results: Six studies comprising 144 patients were included. Over an average follow-up of 17.9 ± 10.5 months, significant improvement in LVEF was observed, increasing from 35 ± 8% prior to upgrade to 48 ± 12% following HPCSP (P < 0.001). Similarly, NYHA class improved from a baseline of 2.7 ± 0.8 to 1.9 ± 0.8 (P < 0.001), indicating meaningful symptomatic relief. Conclusion: Upgrading to His-Purkinje conduction system pacing is a safe and effective strategy in patients with PICM. It offers significant improvements in cardiac function and quality of life by restoring physiologic electrical activation. HPCSP represents a promising alternative to BiVP in this population and should be considered in clinical decision-making for pacing upgrades.

Introduction: Hypercholesterolemia drives atherosclerotic cardiovascular disease. Bempedoic acid (BA) lowers low-density-lipoprotein cholesterol (LDL-C) by inhibiting ATP-citrate-lyase, providing a non-statin option for patients who need additional lipid control. Hypothesis: We expected BA to improve atherogenic lipids and major adverse cardiovascular events (MACE) without raising cardiovascular (CV) mortality and with an acceptable safety profile. Aims: To measure the pooled effect of BA on (1) LDL-C, (2) non-HDL-C, (3) high-sensitivity C-reactive protein (hsCRP) and to compare clinical outcomes for (4) MACE, (5) CV mortality, and (6) hyperuricemia versus placebo. Methods: A systematic search of PubMed, Embase, MEDLINE, Google Scholar and ClinicalTrials.gov through 1 April 2025 identified randomized controlled trials (RCTs) of BA versus placebo in adults with hypercholesterolemia. Data were extracted into a spreadsheet, and analyses were performed with RevMan 5.4. Results: 13 RCT's with 22345 patients met the inclusion criteria. BA produced robust lipid and inflammatory improvements. LDL-C fell by 24.3 % (95 % CI −27.8 to −20.9), non-HDL-C by 19.8 % (95 % CI −25.0 to −14.6), and hsCRP by 26.7 % (95 % CI −39.6 to −13.7). These changes translated into a 19 % relative reduction in MACE (RR 0.81, 95 % CI 0.68–0.96), while CV mortality was unchanged (RR 0.87, 95 % CI 0.53–1.43). As anticipated, hyperuricemia risk almost doubled with BA (RR 1.93, 95 % CI 1.75–2.14). Conclusion: BA consistently lowers LDL-C, non-HDL-C and systemic inflammation and reduces MACE without affecting CV mortality. The main safety concern is higher hyperuricemia, which appears manageable with monitoring. These findings support BA as an effective add-on therapy for patients who are statin-intolerant or need further lipid reduction, while highlighting the need for longer trials to assess mortality benefits and long-term safety.

Background: Coronary computed tomography angiography (CCTA) is vital for diagnosing ischemic heart disease, yet its accuracy is affected by varying reader expertise. Artificial Intelligence (AI)-driven automated stenosis assessment offers promise for enhancing diagnostic consistency. Aim: We aim to evaluate an AI-CCTA assessment against invasive coronary angiography, invasive FFR, and expert readings. Methods: We performed a comprehensive search in Web of Science, Scopus, PubMed, Cochrane Library, and EMBASE from inception until March 2025. Two independent reviewers screened articles and extracted data on study design, patient demographics, AI methodology, stenosis thresholds, and outcomes. For statistical analysis, we constructed summary receiver operating characteristic (SROC) curves and used a bivariate random-effects model to derive pooled sensitivity, specificity, diagnostic odds ratios (DOR), and area under the curve (AUC). Forest plots were generated to visualize these metrics. Results: Our meta-analysis included 34 studies with 10,067 patients. AI-based CCTA demonstrated excellent diagnostic performance with an AUC of 0.932 for per-patient analysis. The pooled per-patient sensitivity was 0.89 (95% CI: 0.87–0.91) and specificity was 0.80 (95% CI: 0.74–0.86), with a DOR of 37.07 (95% CI: 24.57–55.92). AI validated against expert readers achieved the highest accuracy (0.94, 95% CI: 0.87-0.98). The >70% stenosis threshold demonstrated superior performance (accuracy: 0.89, specificity: 0.96) compared to the >50% threshold (accuracy: 0.86, specificity: 0.87). Per-vessel analysis showed comparable results with an AUC of 0.905. Conclusion: Our meta-analysis confirms that AI-assisted coronary CT angiography delivers high diagnostic performance for coronary stenosis detection, with strong AUC values, high sensitivity and specificity, and robust diagnostic odds ratios across both per-patient and per-vessel assessments.

Background: Exhaled volatile organic compounds (VOCs) can provide insight into various physiological and metabolic processes. Aim: The purpose of this study was to determine if exhaled VOCs would differ across disease severity in heart failure (HF) patients. Methods: We recruited 62 individuals who were classified as healthy control (CTL), admissions with fluid overload (DHF), NYHA class I-II or NYHA class II-III. Breath samples were collected using the ReCIVA Breath Sampler (Owlstone Medical Ltd) and analyzed using mass spectrometry and gas chromatography. Typical clinical characteristics were documented at the time of exhaled breath collection. Results: Data were obtained on 16 CTL, 21 DHF, 15 NYHA I-II and 10 NYHA II-III (characteristics shown in Table). For the HF groups, DHF, NYHA I-II and NYHA II-III, the %HPEFF were 32, 63 and 63% respectively. Regarding exhaled VOCs, we observed a stepwise increase in VOCs potentially linked to lipid peroxidation or fatty acid metabolism, such as pent-3-en-2-one, 2-pentanone, and 4-heptanone, as disease severity worsened. A similar trend was seen for sulphur containing compounds (methyl propyl sulfide, allyl methyl sulfide and 1(methyl thiol)-1 propene)), potentially providing insight into impaired hepatic or renal clearance in more advanced HF. The level of methyl pyruvate on breath also rose with increasing disease severity, which may reflect altered energy metabolism. Finally, gut microbiome-related VOCs (acetoin, 2,3-butanediol, and butyric anhydride) increased across severity groups, potentially reflecting dysbiosis in advanced disease. Conclusions: In a small pilot study aiming to identify potential exhaled breath biomarkers in HF, we observed significant differences in VOCs across disease severity. These compounds have been linked to lipid peroxidation, energy metabolism, liver and kidney function as well as microbial fermentation and short-chain fatty acid metabolism. Collectively, these data demonstrate the ability of breath omics to potentially stratify disease severity and provide additional biological insights into HF pathophysiology. Larger studies are needed to determine whether a breath biomarker panel could be established to quantify disease severity and predict decompensation risk in HF.

Background: Ventricular tachycardia (VT) is a major contributor to death among ischemic heart disease (IHD) patients. In this systematic review and meta-analysis, we evaluate the efficacy of catheter ablation in patients with ischemic cardiomyopathy. Methods: We conducted a meta-analysis by searching the electronic database up to April 2025. Seven studies, including 1192 patients, were identified. A random-effect model was used to estimate pooled risk ratios (RRs) and 95% confidence intervals (CIs). Trial sequential analysis was conducted to assess sample size adequacy. Results: Among Ischemic heart disease patients with ICDs, VT ablation was associated with a significant reduction in ICD shocks (RR = 0.50, 95% CI [0.34–0.74]), a trend toward reduced VT storm (RR = 0.64, 95% CI [0.40–1.04], p = 0.07), and lower rates of cardiovascular hospitalization (RR = 0.73, 95% CI [0.53–1.01], p = 0.06) compared to ICD alone. However, no significant differences were observed when compared to patients receiving ICD plus antiarrhythmic drugs (AADs). Additionally, VT ablation showed no significant impact on mortality or VT/VF recurrence compared to either ICD alone or ICD with AADs. Trial Sequential Analysis provided conclusive evidence for VT/VF recurrence outcomes, while further data are required for other outcomes. Conclusion: Among ischemic heart disease patients with ICD, VT ablation reduces ICD shocks, VT storm, and cardiovascular hospitalizations compared to ICD-only, but offers no significant advantage over ICD combined with antiarrhythmic drugs. VT ablation does not impact mortality or the recurrence of VT/VF. Trial Sequential Analysis confirmed conclusive evidence for VT/VF recurrence, while additional data is needed for other outcomes.

Background: Atrial arrhythmia recurrence after surgical ablation remains challenging to predict and integrating novel biomarkers may improve risk stratification. Objective: To evaluate whether combining preoperative transthoracic echocardiography (TTE) with artificial intelligence-enabled ECG (AI-ECG) scores enhances prediction of atrial fibrillation/flutter (AF/AFl) recurrence post surgical ablation. Methods: We retrospectively analyzed 1,696 patients undergoing Surgical AF/AFl Ablation between 2006 and 2025 with preoperative TTE and post-blanking ECGs. Clinical variables, TTE indices, and AI-ECG scores (AF probability, ECG-estimated age, HFpEF, LV dysfunction, and aortic stenosis scores) were assessed. The primary outcome was time to AF/AFl recurrence. Univariate/multivariable Cox models and a Random Survival Forest (RSF) model (80:20, training: testing) were developed to identify predictors. Results: Of 1,696 patients (mean age 67.3±10.2 years; 61.7% male) undergoing surgical AF/AFl ablation, 949 (56%) experienced AF/AFl recurrence during a median follow-up of 3.14 years. Patients with recurrence had larger left atria (mean LA area 30.4 vs 24.5 cm 2 , p < 0.001), more diastolic dysfunction (mitral inflow E-wave velocity 1.015 m/s vs 0.896 m/s , p < 0.001), and adverse AI-ECG biomarkers. In multivariable analysis, independent predictors of recurrence included a higher ECG-AF score (p < 1 x 10 -300 ), an older AI-ECG age (p = 0.0002), LA area (p = 0.046), body mass index (p = 0.036), and elevated diastolic blood pressure (HR 1.008 per mmHg, 95% CI 1.002 – 1.014; p = 0.010). The final Cox model achieved a C-index of ~0.67 and stratified patients into risk quartiles with 3-year freedom-from-arrhythmia rates of ~85% (lowest-risk) vs ~43% (highest-risk). An RSF model yielded a slightly higher test C-index (≈0.69), suggesting modest improvement with non-linear modeling. Conclusions: Preoperative AI-ECG biomarkers (AF probability, age discordance) and TTE markers of atrial remodeling independently predicted AF/AFl recurrence after surgical AF/AFl ablation and integration of these metrics improved risk stratification.

Introduction: Acute respiratory distress syndrome (ARDS) is characterized by pulmonary edema, hypoxia and systemic inflammation. The presence and clinical implications of a high cardiac output state in patients with ARDS remain unknown given the lack of invasive hemodynamic monitoring in most patients with ARDS. Hypothesis: A subset of patients with ARDS will have high output heart failure with high cardiac output and elevated pulmonary capillary wedge pressure (PAWP) representing a unique subphenotype of ARDS. Methods: Patients from the Comparison of Two Fluid-Management Strategies in Acute Lung Injury (FACTT) Trial were stratified according to baseline cardiac output states and filling pressures: HOLHF (high-output with left heart failure) was defined as cardiac index (CI) ≥ 4 L/min/m 2 and PAWP ≥ 15 mmHg; HOnoLHF (high-output without left heart failure) as CI ≥ 4 L/min/m 2 and PAWP < 15 mmHg; and NOHO (non-high-output) as CI < 4 L/min/m 2 . Hemodynamics, oxygenation, metabolic demand (VO 2 ) and clinical outcomes were compared across groups. Results: Of the 399 patients included, high-output states were present in 52% of all patients (Figure 1). High-output cohorts demonstrated higher myocardial workload, lower systemic vascular resistance (SVR), lower pulsatile arterial load, higher VO 2 and more impaired systemic O 2 utilization despite the highest peripheral O 2 delivery compared to NOHO (Table). Among the high-output cohorts, the HOLHF cohort demonstrated higher right ventricular stroke work (25.2 ± 12.1 vs. 20.3 ± 12.3, P<0.001), worse A-a gradient (326.0 ± 136.5 vs. 276.1 ± 114.7, P=0.048) and higher VO 2 (382.3 ± 234.2 vs. 289.8 ± 171.7, P<0.001) compared to HOnoLHF. Increasing cardiac output was individually related to decreasing SVR (r=-0.742, P<0.001) and increasing VO 2 (r=0.565, P<0.001) (Figure 2). When adjusted, both variables remained strongly related to increasing cardiac output (P<0.001). There were no significant differences among the cohorts with respect to refractory hypoxia and mortality. Conclusions: High-output states in ARDS are prevalent and underrecognized. Such states appear to be driven by arterial vasodilatation and heightened VO 2 with additional manifestations of increased myocardial workload and inefficient peripheral utilization with impaired systemic O 2 utilization. Whether specific strategies to mitigate the high output state might improve gas exchange, hypoxia and outcomes in patients with HOLHF and ARDS requires further study.

Background: Pulsed field ablation (PFA) has become a cornerstone for atrial fibrillation ablation. Multiple platforms have been developed and approved worldwide, and routine screening for asymptomatic brain injury (ABI) has been included in several trials as part of the safety assessment of this technology. The incidence by catheter/platform, predictors of occurrence, and clinical impact remain incompletely understood. Research Question: In patients with atrial fibrillation undergoing pulmonary vein isolation, does the incidence of ABI vary between different PFA platforms? Methods: We searched the MEDLINE/PubMed, Embase, and Cochrane Central Register of Controlled Trials databases for studies reporting on patients who underwent PFA and post-procedure brain MRI to screen for ABI. The review was conducted in accordance with PRISMA guidelines. A random-effects proportion meta-analysis was performed, with subgroup analysis based on the PFA platform used. For studies including a thermal ablation control group, risk ratio (RR) was used to compare outcomes. Finally, a meta-regression was conducted to identify potential predictors of ABI incidence. Results: A total of 19 studies reporting data from 742 patients who underwent post-ablation brain MRI were included in this review. The pooled incidence of silent cerebral events (new findings visible only on DWI sequences) and silent cerebral lesions (new findings on both DWI and FLAIR sequences) was 5% each (95% CI, 3%–8%). The pooled incidence of any ABI was 10% (95% CI, 8%–13%). A platform-level subgroup analysis demonstrated comparable outcomes across the platforms with available data (Figure 1). The meta-regression included age, sex, CHA2DS2-VASc score, and incidence of symptomatic stroke/TIA, but no statistically significant associations were identified. In the four studies that included a thermal ablation control group, there was no significant difference in ABI incidence between PFA and thermal ablation (RR: 1.37; 95% CI, 0.68–2.74; P = 0.38; I2 = 16%) (Figure 2). Seven studies reported follow-up MRI in patients who presented with an ABI. Among 20 patients with ABI after ablation, radiologic lesions persisted in 2 patients. Conclusion: ABI is a relatively frequent finding following PFA; however, current evidence does not reveal significant differences between available platforms. Radiologic findings tend to be transient, suggesting a limited long-term clinical impact.

Background: Voltage-gated Nav1.5 channel, encoded by SCN5A , is essential for initiation and propagation of action potentials (AP) in atria. Nav1.5 channelopathy is strongly associated with arrhythmogenesis, including atrial fibrillation. Sorbin and SH3 domain-containing protein 2 (Sorbs2), encoded by SORBS2 , is an important cytoskeletal protein for maintaining atrial structural and electrical integrity. However, the specific mechanisms through which Sorbs2 modulates Nav1.5 function in atria is unknown. Hypothesis: Sorbs2 modulates atrial Nav1.5 expression and function through direct protein-protein interaction. Methods: We created the cardiac-specific Sorbs2 knockout ( c-Sorbs2 KO) mice. We determined the mechanisms by which Sorbs2 regulates Nav1.5 channel expression and function by performing electrophysiological experiments using atrial cells and tissues from control and c-Sorbs2 KO mice, in conjunction with molecular biological studies and in silico analysis. Results: c-Sorbs2 KO mice at 8-10 months showed marked left atrial (LA) enlargement, and ECG showed significantly prolonged P-R durations. Compared to wild-type controls, intracellular recordings in LA tissues isolated from c-Sorbs2 KO mice showed reduced AP amplitude, decreased upstroke velocity, prolonged AP duration at 90% repolarization and effective refractory period, spontaneous atrial tachycardias and triggered activity. Patch-clamp recordings in freshly isolated atrial cardiomyocytes showed a significantly reduced peak sodium current density in c-Sorbs2 KO mice (-12.0 ± 1.6 pA/pF at -45 mV, n = 10), compared to controls (-21.3 ± 4.0 pA/pF at -45 mV, n = 12, p < 0.05). Also, the steady-state activation and inactivation curves of Nav1.5 channel were rightward shifted in c-Sorbs2 KO atrial cardiomyocytes. Molecular docking analysis showed that the Sorbs2 SH3 domain interacts directly with the voltage-sensing domain of Nav1.5. Co-immunoprecipitation assays confirmed the physical interactions between Nav1.5 and the C-terminal SH3 domain of Sorbs2. Furthermore, results from membrane biotinylation study demonstrated that deletion of the SH3 domains of Sorbs2 significantly reduced Nav1.5 surface expression in HEK293 cells. Sorbs2 interacts directly with Nav1.5 through its SH3 domain, playing a key role in regulating Nav1.5 channel gating kinetics and surface expression in atrial cardiomyocytes. Loss of Sorbs2 results in Nav1.5 channelopathy and contributes to atrial electrical remodeling.