Background: Janus kinase inhibitors (JAKis) are an integral aspect of the management of myeloproliferative neoplasms (MPNs). Part of the clinical benefit derived from JAKis may be due to reductions in thrombosis, a potentially life‐threatening complication of MPNs. However, evidence has emerged of adverse cardiovascular effects secondary to JAKis. We conducted a first‐of‐a‐kind meta‐analysis of the cardiovascular safety of JAKis in the treatment of MPNs.Methods: This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRISMA). Systematic searches for studies comparing JAKi treatment to a control group were conducted. Studies reporting hypertension, major adverse cardiovascular events (MACE) and thromboembolic events were included in a meta‐analysis using a random‐effects model for the primary analysis, and fixed‐effects model for any subgroup analyses performed.Results: A total of 23 publications, consisting of nine clinical trials and one retrospective analysis, met the inclusion criteria. This resulted in a pooled population of 2198 patients (JAKi n = 1145, Control n = 1053). In studies reporting thromboembolic events (n = 9), pooled analysis revealed a significantly lower rate of thromboembolic events in the JAKi group (incidence rate ratio (IRR): 0.52, 95% CI: 0.28–0.98, p = 0.04). This was primarily driven by ruxolitinib studies in myelofibrosis (MF) and polycythemia vera (PV) as when a subgroup analysis of these trials was performed (n = 7), an even more significant reduction in thromboembolic events with JAKi treatment was found (IRR: 0.41, 95%CI: 0.26–0.64, p < 0.001). There was no significant difference in MACE or hypertension between JAKi and control groups.Conclusion: This meta‐analysis suggests that JAKi treatment of MPN was associated with a reduced risk of thromboembolic events; primarily driven by studies of ruxolitinib in PV and MF. Further prospective clinical trials are warranted to confirm these findings and characterise the cardiovascular profile of other JAKis and other types of MPNs.

OBJECTIVES: Right ventricular-to-pulmonary artery coupling has been associated with outcomes in mitral regurgitation treated by transcatheter approaches. We evaluated right ventricular-to-pulmonary artery coupling as a predictor of survival and postoperative length of hospital stay (LOS) in patients with mitral regurgitation undergoing mitral valve surgery. METHODS: In this retrospective analysis (median follow-up: 5.8 years), right ventricular-to-pulmonary artery coupling was quantified as the ratio of tricuspid annular plane systolic excursion to pulmonary artery systolic pressure (TAPSE/PASP) using transthoracic echocardiography. Receiver operating characteristic curve analysis was used to determine the optimum cut-point of TAPSE/PASP to predict all-cause mortality, and the study population was dichotomized according to this value. The primary end point was all-cause mortality. A secondary end point of LOS was also assessed. RESULTS: Out of 142 patients (median age: 67, female: 49%), 35 showed impaired coupling at baseline (TAPSE/PASP ≤0.35). Patients with TAPSE/PASP ≤0.35 had higher absolute mortality (37% vs 8%, P < 0.001) and longer LOS (7 days vs 9 days, P = 0.04). Kaplan–Meier analysis revealed lower survival in patients with TAPSE/PASP ≤0.35 (log-rank: P < 0.0001). In multivariable Cox regression, TAPSE/PASP ≤0.35 was the most significant predictor of all-cause mortality (hazard ratio: 3.69, 95% confidence interval 1.31–10.1, P = 0.011), alongside chronic obstructive pulmonary disease and estimated glomerular filtration rate. TAPSE/PASP ≤0.35 was associated with significantly increased LOS (β: 4.6, 95% confidence interval 0.66–8.5, P = 0.022) alongside left ventricular ejection fraction, mitral valve replacement and urgent operation. CONCLUSIONS: In mitral regurgitation patients undergoing mitral valve surgery, TAPSE/PASP ≤0.35 is associated with increased mortality and LOS. Further validation is indicated in larger, prospective cohorts.

Background/Objectives: Contrast-induced acute kidney injury (AKI) is associated with early mortality and adverse events. However, in the setting of transcatheter aortic valve implantation (TAVI), previous literature has failed to establish a correlation between the absolute volume of contrast media administered and mortality. We aimed to investigate the impact of contrast volume administered normalised to estimated glomerular filtration rate (CV/eGFR) on the development of AKI and on 30-day all-cause mortality in TAVI patients. Methods: We retrospectively analysed a cohort of 1150 patients who underwent TAVI at our unit between 2015 and 2018. Results: Follow-up was complete for 1064 patients. There were 23 deaths within the follow-up period and 76 cases of AKI, 9 of which required new renal replacement therapy (RRT). Receiver-operating characteristic (ROC) curve analysis showed fair discrimination for 30-day all-cause mortality at a CV/eGFR ratio of 3.6 (area under the ROC curve (AUC) 0.671). Of patients in whom CV data were available, 86.0% (n = 757) had a CV/eGFR < 3.6 and 14.0% (n = 123) had a CV/eGFR ≥ 3.6. In multivariate logistic regression analysis, CV/eGFR ≥ 3.6 was the strongest predictor of 30-day all-cause mortality (odds ratio 5.06, 95% confidence interval [1.61–15.7], p = 0.004). Other independent predictors were procedural urgency (3.28 [1.04–10.3], p = 0.038) and being under general anaesthesia (4.81 [1.10–17.3], p = 0.023). CV/eGFR ≥ 3.6 was also independently associated with significantly increased odds of AKI (2.28 [1.20–4.17], p = 0.009) alongside significant non-left main stem coronary artery disease (2.56 [1.45–4.66], p = 0.001), and diabetes (1.82 [1.03–3.19], p = 0.037). In supplementary ROC curve analysis, a similar CV/eGFR cut point of 3.6 was found to be an excellent predictor for new RRT (AUC 0.833). Conclusions: In conclusion, a CV/eGFR ≥ 3.6 post-TAVI was found to be a strong predictor of 30-day mortality and AKI. The maximum contrast volume that can be safely administered in each patient without significantly increasing the risk of mortality and AKI can be calculated using this ratio.

Background/Objectives: Sex-related differences in the presentation and outcomes of patients with mitral regurgitation (MR) undergoing mitral valve (MV) surgery remain unclear. We aimed to identify these differences to inform personalized management. Methods: A total of 143 consecutive patients undergoing surgery for MR between 2017 and 2018 were stratified by sex and assessed for differences in characteristics. We performed 1:1 propensity score matching (PSM) by sex, with baseline characteristics as covariates, yielding 38 comparable pairs which were analyzed for differences in all-cause mortality and post-operative length of stay (LOS). Results: Females (n = 67) were more symptomatic (NYHA Class ≥ 3: 73% vs. 45%, p < 0.001), had higher logistic EuroSCORE (5.5 vs. 3.9, p = 0.006), had more urgent operations (25% vs. 11%, p = 0.020), MV replacements (28% vs. 11%, p = 0.007), and secondary MR (43% vs. 16%, p < 0.001). Females had significantly smaller end-diastolic and end-systolic left ventricular (LV) diameters, though indexed diameters showed no significant differences. After PSM, females had significantly longer LOS (7 days vs. 9 days, p = 0.033) and no differences in long-term mortality (hazard ratio [HR]: 1.25, 95% confidence interval [CI]: 0.34–4.76, p = 0.7, median follow-up: 6.67 years). An indexed LV end-systolic diameter (LVESDi) > 19 mm/m² yielded greater specificity (46.0% vs. 26.7%) and comparable sensitivity (69.4% vs. 69.2%) to LVESD > 40 mm. In subgroup analyses, female patients undergoing concomitant tricuspid intervention (HR: 6.80 [1.63–37.92], p < 0.01) or urgent operation (HR: 4.85 [1.08–21.06], p = 0.04) had worse prognoses than males. Conclusions: Females undergoing MV surgery for MR had more symptoms, higher surgical risk, and longer LOS, but similar mortality compared to males. However, concomitant tricuspid intervention and urgent operations were associated with higher mortality. Our results add to the growing body of evidence that current non-indexed LV diameter thresholds may not adequately account for sex differences.

Purpose of Review: Cardiorenal syndrome type 4 (CRS-4) is characterised by the development of cardiac dysfunction secondary to chronic kidney disease (CKD). This review outlines the pathophysiology of CRS-4, with a focus on the emerging role of mitochondrial dysfunction, and evaluates novel mitochondria-targeting therapeutics for CRS-4. Recent Findings: Current research has positioned mitochondrial dysfunction in cardiomyocytes as a key driver of CRS-4 pathophysiology, characterised by impaired adenosine triphosphate production, increased reactive oxygen species (ROS) generation, dysregulated mitophagy, altered mitochondrial biogenesis and dynamics, and bioenergetic malfunction. Currently licensed drugs, such as dapagliflozin and sacubitril/valsartan, have demonstrated mitoprotective effects in CRS-4, and numerous other therapies targeting mitochondria have proven efficacious in preclinical studies. However, real-world clinical trials are required to determine whether mitochondria represent a viable therapeutic target that offers meaningful clinical benefits to patients with CKD. Summary: There is increasing evidence that mitochondrial dysfunction is a key pathomechanism in the development of CRS-4. Mitochondrial-targeting therapies offer a novel mechanism-driven approach, with numerous showing preclinical promise. However, real-world clinical trials are required to determine their therapeutic potential.

Evidence on sex differences in outcomes after interventions for primary mitral regurgitation (PMR) remains conflicting. The authors performed a dedicated meta-analysis to examine whether guideline-recommended thresholds for intervention may contribute to these discrepancies. Electronic databases were searched for studies reporting long-term outcomes of patients undergoing surgical or transcatheter interventions for PMR, stratified by sex. The primary endpoint was all-cause mortality, and the secondary endpoint was major adverse cardiovascular events. Reconstructed time-to-event individual patient data were used to derive frailty-adjusted Cox models and restricted mean survival time. To investigate whether sex-based differences in baseline characteristics had a modulating effect on differences in all-cause mortality, meta-regression was performed on individual patient data-derived HRs using a linear mixed-effects model. Across 17 studies (N = 25,690), women comprised the minority (n = 9,632, 37.5%) and were significantly older (mean difference: 3.2 years, 95% CI: 2.2-4.3) with a greater proportion of heart failure symptoms (OR: 1.8; 95% CI: 1.6-2.1). At 15.7 years of follow-up, women had significantly greater risk of all-cause mortality compared with men (HR: 1.15; 95% CI: 1.07-1.24), corresponding to a survival deficit of 5.8 months (95% CI: 3.7-7.7). Similar results were observed in sensitivity analyses restricted to surgical intervention studies (HR: 1.18; 95% CI: 1.10-1.27). Female sex was also associated with significantly increased major adverse cardiovascular events (n = 2,775) (HR: 1.37; 95% CI: 1.11-1.70; Δ restricted mean survival time: 8.5 months, 95% CI: 2.4-14.5). Age, ≥ moderate tricuspid regurgitation (TR), and concomitant tricuspid valve repair (TVr) emerged as significant moderators of sex differences in mortality after intervention for PMR (P < 0.001, P = 0.03, and P < 0.001, respectively). A greater proportion of ≥ moderate TR and TVr in women conferred increased mortality relative to men. Neither left ventricular nor left atrial parameters significantly moderated sex differences in all-cause mortality (all P > 0.05). At the time of PMR intervention, women are older, have more symptoms, and worse long-term outcomes compared with men. Older female age alongside higher prevalence of ≥ moderate TR and TVr explained a significant proportion of this heterogeneity in sex-related all-cause mortality, whereas differences in left ventricular and left atrial parameters had no significant influence. A careful appraisal of current guidelines to ensure equality of health care outcomes between sexes is warranted.