Citations

BACKGROUND: Chronic aortic regurgitation (AR) is associated with significant cardiac remodeling, but the prevalence and prognostic impact of extravalvular cardiac damage remain unexplored. METHODS: Adults with moderate or greater chronic AR identified on echocardiogram between January 2008 and July 2024 were included. Exclusion criteria were acute AR, hypertrophic and infiltrative cardiomyopathies, prior cardiac surgery, and valve stenosis. Cardiac damage was classified into hierarchical stages: no cardiac damage (stage 0), left ventricular damage (stage 1), moderate or greater mitral regurgitation or left atrial enlargement or atrial fibrillation (stage 2), pulmonary hypertension or moderate or greater tricuspid regurgitation (stage 3), and significant right ventricular dysfunction (stage 4). The primary outcome was the association between cardiac damage stages and all-cause mortality under medical surveillance. RESULTS: Of 4026 patients (median age, 72 [61–80] years), 78% had moderate AR, 11% had moderate-severe, and 11% had severe AR. Cardiac damage was present in 87% of patients: 14% in stage 1, 53% in stage 2, 18% in stage 3, and 2% in stage 4. In a multivariable model, including age, sex, AR severity, and Charlson Comorbidity Index, cardiac damage stages were associated with mortality. Adjusted hazard ratios were 1.42 (95% CI, 1.04–1.96) for stage 1, 1.58 (95% CI, 1.21–2.06) for stage 2, 2.78 (95% CI, 2.10–3.67) for stage 3, and 5.34 (95% CI, 3.67–7.76) for stage 4. Adding cardiac damage staging to multivariable models improved predictive accuracy for mortality, increasing the concordance statistics from 0.73 (95% CI, 0.71–0.75) to 0.76 (95% CI, 0.74–0.77). CONCLUSIONS: Cardiac damage is present in nearly 90% of patients with moderate or greater AR and is associated with increased mortality, highlighting the need for a more comprehensive evaluation of cardiac structure and function beyond the aortic valve and left ventricle.

Abstract While the clinical focus on the sentinel lymph node biopsy (SLNB) is the presence of intra- or extra-nodal metastases, preclinical studies suggest that tumor-draining SLNB-associated vascular architecture and adhesion properties are altered regardless of SLNB positivity. Human intravital microscopy (HIVM) has defined blood vessel abnormalities that may impact lymphocyte adhesion and systemic drug delivery at primary melanoma sites. In this pilot study of HIVM during melanoma SLNB, we sought to determine the feasibility of obtaining HIVM observations of SLNB-associated vessels. We successfully performed HIVM in all 20 SLNB patients, and 7 were found to have nodal micrometastases by standard pathology. HIVM was capable of identifying both functional and non-functional SLNB-associated vessels based on the presence or absence of fluorescent dye uptake, respectively. Comparing vessel characteristics as a secondary objective, no statistically significant differences were noted in the diameter, flow rate, functionality, or shear stress of SLNB-associated blood vessels between positive and negative SLNBs, which may likely have been a reflection of the minimal disease burden. Nonetheless, these initial observations provide the framework to optimize future trials of HIVM in cancer patients.

ABSTRACT Pharmacists play a critical role in optimizing medication use, especially in vulnerable populations such as those with chronic kidney disease (CKD). Despite strong evidence and recent guideline endorsements, many pharmacists continue to rely on the Cockcroft–Gault (C‐G) equation for medication dosing. This opinion paper issues a call to action for the widespread adoption of a race‐free, body surface area–adjusted estimated glomerular filtration rate (eGFR BSAadj ) for medication‐related decision‐making, as endorsed by the 2024 Kidney Disease: Improving Global Outcomes CKD guidelines and the National Kidney Foundation and the American Society of Nephrology Taskforce. Persistent variability in pharmacy practice, institutional protocols, and pharmacy education underscores the need for coordinated change. We urge health systems to integrate eGFR BSAadj into electronic health records and clinical decision support to enhance medication decision‐making; institutions to align protocols with contemporary eGFR‐based prescribing standards; pharmacy educators to contemporize and standardize education on kidney function assessment and medication dosing; and regulatory bodies to update licensure and board examinations. The pharmacy profession must act decisively in order to align with evidence‐based, equitable kidney‐related dosing practices and ensure optimal medication management for all patients.

Importance Assisted ventilation during delayed cord clamping (DCC) may improve the physiologic transition of extremely preterm infants immediately after birth. Objective To determine whether assisted ventilation during 120 seconds of DCC was associated with reduced higher-level resuscitative interventions (intubation, chest compressions, or epinephrine administration) compared with DCC for 30 to 60 seconds followed by resuscitation. Design, Setting, and Participants This was a secondary analysis of the VentFirst randomized clinical trial that was conducted from September 2, 2016, through February 21, 2023, at 12 centers in the US and Canada. Infants born at 23 weeks 0 days’ to 28 weeks 6 days’ gestational age (GA) were included. Intervention Infants randomized to the intervention received either positive-pressure ventilation or continuous positive airway pressure from 30 to 120 seconds after birth, followed by umbilical cord clamping. Those randomized to control received 30 to 60 seconds of DCC followed by assisted ventilation. Main Outcomes and Measures The main outcome was the odds of higher-level resuscitative interventions in the delivery room (DR). Intention-to-treat analyses within 2 a priori cohorts (infants breathing well and not breathing well 30 seconds after birth) used the Cochran-Mantel-Haenszel method to estimate the odds ratios (ORs) of intervention vs control. Results All 570 infants enrolled in the trial were included. Infants had a median (IQR) GA of 26.6 (25.2-27.9) weeks and 273 (47.9%) were female. A total of 271 infants (47.5%) were assessed as not breathing well 30 seconds after birth (150 intervention and 121 control), and 299 (52.5%) were assessed as breathing well 30 seconds after birth (128 intervention and 171 control). In the not-breathing-well cohort, 146 infants (53.9%) were intubated in the DR, 4 received chest compressions (2 intervention and 2 control), and 1 received epinephrine (control). Intubation was less frequent in the intervention group (71 infants [47.3%] vs 75 infants [62.0%]; OR, 0.52; 95% CI, 0.30-0.89). When adjusted by GA strata at randomization, infants in the 26 to 28 weeks’ GA stratum who were in the intervention group were less likely to be intubated in the DR (18 of 79 infants [22.8%] vs 29 of 60 infants [48.3%]; OR, 0.32; 95% CI, 0.15-0.65). However, there was no difference in intubation rates for infants in the 23 to 25 weeks’ GA stratum (53 of 71 infants [74.7%] vs 46 of 61 infants [75.4%]; OR, 0.96; 95% CI, 0.44-2.12). Among infants breathing well at 30 seconds, 74 (24.7%) were intubated in the DR, and none received compressions or epinephrine. Intubation rates were similar between intervention and control in the breathing-well cohort. Conclusions and Relevance While the VentFirst trial did not find a difference in death or intraventricular hemorrhage, this secondary analysis found that assisted ventilation during DCC was associated with less intubation in the DR, primarily among infants born at 26 to 28 weeks’ gestation who were not breathing well 30 seconds after birth. Additional studies are needed before implementing assisted ventilation during DCC in clinical practice. Trial Registration ClinicalTrials.gov Identifier: NCT02742454

ABSTRACT Background and hypothesis End-stage renal disease patients require peritoneal dialysis (PD) as a life-saving therapy; however, they continue to experience systemic inflammation and increased cardiovascular pathology. These complications can be exacerbated by exposure to PD solutions (PDS) containing glucose. This highlights the clinical unmet need for novel osmotic agents to replace glucose. Here, we tested troxerutin, a Food and Drug Administration–approved drug, as a potential osmotic agent. Methods To evaluate troxerutin osmotic and non-toxic effects, in vitro and in vivo experiments were carried out using artificial membranes, mice and cultured human mesothelial cells (MCs). The local and systemic consequences of chronic peritoneal exposure to PDS associated to renal insufficiency were investigated in a preclinical model. 5/6 nephrectomized C57BL/6J mice were daily exposed to glucose- or troxerutin-PDS for 60 days, then evaluating tissue damage, proinflammatory markers and cardiac damage. Results In vitro and in vivo studies revealed that troxerutin exhibits similar osmotic and ultrafiltration capacities to glucose, but with colloidal properties. Moreover, only glucose, but not troxerutin, reduced MC viability, induced mesothelial-to-mesenchymal transition, and increased damage markers (such as interleukin-6 and vascular endothelial growth factor A). In the preclinical model, long-term treatment with glucose-PDS, but not troxerutin-PDS, significantly increased peritoneal membrane thickening, tissue proinflammatory markers (evaluated in peritoneum, kidney, heart and aorta) and cardiovascular damage (cardiac hypertrophy and fibrosis) in mice. These preclinical data clearly demonstrate the wide deleterious effects of chronic peritoneal exposure to glucose-containing PDS in mice with kidney insufficiency and that the replacement of glucose with troxerutin notably reduces these effects. Conclusion Troxerutin emerges as a more biocompatible alternative to glucose as an osmotic agent for PD therapy, exhibiting no adverse local or systemic side effects in preclinical studies. This research presents a novel approach to reduce cardiovascular complications of PD in end-stage kidney disease.

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous entity including patients with different phenotypes of near normal, normal, and supernormal left ventricular (LV) function. Objectives To assess the value of resting LV elastance (also known as force) with transthoracic echocardiography (TTE) to identify HFpEF phenotypes. Methods In a prospective, observational, multicenter study, 2380 HFpEF patients were recruited from July 2016 to May 2024. Systolic blood pressure (SBP) was measured. We assessed LV end-diastolic volume (EDV), end-systolic volume (ESV), EF, force (SBP/ESV), stroke volume (SV), arterial elastance (AE), ventricular-arterial coupling (VAC), and left atrial volume index (LAVI). Global longitudinal strain (GLS) was available in 1164 (48.9%) patients. 680 patients finished follow-up with a composite end-point of major adverse cardiac events (MACEs). Patients were divided into three groups: low force (< 25th percentile, Group 1, < 3.24 mmHg/ml), intermediate force (≥ 25th percentile and ≤ 75 thpercentile, Group 2, 3.24-5.48 mmHg/ml), and high force (> 75 th percentile, Group 3, >5.48 mmHg/ml). Results The 3 groups showed a gradient with descending values (Group 3>2>1) for SBP, EF, GLS, AE, and VAC, with the opposite gradient (Group 1> 2> 3) for EDV, ESV, SV, and LAVI values (all P<0.01). After a median follow-up of 16 months, 205 MACEs occurred in 138 patients. Cumulative MACEs rate was lowest in group 2 (14.7% person-year), higher in group 1 (16.1% person-year) and 3 (22.9% person-year, log rank p = 0.036). Conclusions HFpEF patients present with different LV contractile phenotypes, easily identified with resting LV force and volumetric TTE. The dominant hemodynamic feature of hypocontractile phenotype is a preload recruitment with larger LV EDV and normal SV, while the hypercontractile phenotype is characterized by a small LV with reduced SV. The hypercontractile and hypocontractile phenotypes are associated with a higher risk of subsequent events.

Abstract Backgrounds Transthoracic echocardiography (TTE) identifies a peculiar hypercontractile phenotype (HP) in patients with heart failure and preserved ejection fraction (HFpEF) with high resting left ventricular (LV) elastance (also called force). Objectives To assess the functional response and its prognosis associated with HP in HFpEF by stress echocardiography (SE). Methods In a prospective, observational, multicenter study, 1213 patients with HFpEF were divided into two groups based on the highest quartile of rest force: non-hypercontractile phenotype group (non-HP, < 5.64 mmHg/mL, Group 1, n= 910), and HP group (≥5.64 mmHg/mL, Group 2, n= 303). All patients underwent SE with at least 4 of the following stress parameters assessed: wall motion score index (WMSI), B-lines (4-site score), force-based LV contractile reserve, coronary flow velocity reserve (CFVR), and heart rate reserve (HRR). The employed stress was exercise (n=687), dobutamine (n=195), or vasodilators (n=331). SE score ranged from 0 (all steps normal) to 1-5, according to the number of abnormal steps. Follow-up was completed in a subset of 260 patients. Results The 2 groups showed similar values of peak stress WMSI but the global functional burden was higher in Group 2 patients: see table. In a subset of 260 patients who finished follow-up, there were 212 non-HP patients and 48 HP patients. During a median follow-up of 15 months (interquartile range: 10-20), 26 deaths, 20 heart failure (HF) rehospitalizations, and 64 major adverse cardiovascular events (MACEs) occurred. The cumulative HF rehospitalization rate and MACEs rate were higher in HP group (log-rank p<0.01): see figure. Rest force (HR, 1.17; 95% CI: 1.06-1.29; P: 0.040), rest SPAP (HR, 1.08; 95% CI: 1.02-1.14; P: 0.007) and ABCDE score (HR, 1.15; 95% CI: 1.01-1.66; P: 0.032) were independently associated with MACEs. Conclusions HFpEF patients with HP are functionally weaker with multiple vulnerabilities during stress and at higher risk of subsequent events compared to non-HP patients.Relation between resting values of force

Abstract Background Elevated left ventricular filling pressure (LVFP) is associated with an increased risk of heart failure and mortality. Pulmonary artery wedge pressure (PAWP) is considered the gold standard for assessing LVFP. Recently, we validated an artificial intelligence-enabled electrocardiogram (AI-ECG) to assess LV diastolic function (LVDF) and LVFP. Herein, we compare AI-ECG with PAWP in predicting long-term mortality. Methods We included adults who had comprehensive echocardiography with available ECG within 14-days and right-heart-catheterization (RHC) within 30-days of echocardiography. Elevated-LVFP was defined as PAWP>15 mmHg by RHC, grades 2-3 LVDF by echocardiography, or as adjudicated by the AI-ECG algorithm. Prognosis by AI-ECG was compared to that by echocardiography and PAWP. Results Among 4,168 patients (median age 64 years, 47.7% female), 1,841 had normal-LVFP, and 2,327 had elevated-LVFP by RHC. Echocardiography classified 1,502 patients as normal-LVFP, 1,643 as elevated-LVFP, and 1,023 as indeterminate-LVFP. AI-ECG demonstrated an area-under-the-curve of 0.879 (95%-confidence-interval 0.867-0.891) for predicting elevated-LVFP as determined by echocardiography and 0.742 (95%-confidence-interval 0.724-0.759) for predicting elevated-LVFP as determined by RHC. Over a median follow-up of 7.7 years, 2,735 (34.4%) patients died. In multivariable models, elevated-LVFP by any modality was associated with an increased risk of death (AI-ECG: adjusted-hazard-ratio 1.80, 95% confidence-interval 1.55-2.09; echocardiography: adjusted-hazard-ratio 1.74, 95% confidence-interval 1.51-2.02; PAWP: adjusted-hazard-ratio 1.26, 95% confidence-interval 1.11-1.43). AI-ECG-derived LVFP provided incremental prognostic discrimination compared to echocardiography- or RHC-derived LVFP. Conclusions AI-ECG-derived LVFP offers an accessible, affordable, and noninvasive alternative for detecting elevated LVFP, with potential independent prognostic value beyond traditional echocardiographic and invasive assessments.Survival across LVFP concordance

Background: The arteriovenous fistula (AVF) is a requirement for hemodialysis therapy in end-stage kidney disease (ESKD) patients. A consequence of AVF creation is compensatory cardiovascular hemodynamics, which are subsequently associated with cardiac remodeling. Relatedly, cardiovascular mortality and morbidity are elevated in ESKD patients, which worsens in dialysis patients. Currently, no suitable uremic large animal models exist to investigate the underlying mechanisms of AVF-induced cardiac remodeling. Research Question: This study aims to characterize cardiovascular changes secondary to AVF creation, supported by percutaneous transluminal angioplasty (PTA), in a uremic pig model. Methods: Chronic kidney disease (CKD) was induced via renal embolization, followed by AVF creation 28 days later. The AVF was created by anastomosis of the left common carotid artery to the left external jugular vein. AVF stenosis was alleviated 28 days thereafter via PTA, and cardiac MRI was performed at 14-, 28-, and 42-days post-PTA. Results: Increased end-diastolic volumes were observed in the left and right ventricles at day 42 vs 14 (200.8ml to 249.5ml, p=0.0457, and 204.6ml to 260.0ml, p=0.0268 respectively), while systolic function was preserved. Left ventricle (LV) stroke volume and blood flow through the aorta, pulmonary artery, and vena cava were also increased. In perivascular areas of the free wall of the LV at day 42 vs control, senescence markers showed increased p16 expression (fold change 10.21, p=0.0086) and decreased p21 expression (fold change 0.07, p=0.0357). The LV showed perivascular fibrosis (0.2% to 0.59%, p=0.021), via picrosirius red, reduced collagen-type IV expression (fold change 0.81, p=0.0089), and increased MMP2 levels (fold change 14.33, p=0.0213). Cardiomyocyte cross-sectional area was increased (from 800.9 µm 2 to 1250.0 µm 2 , p=0.0296), without CD4+ or CD68+ cell LV infiltration. Conclusion: In conclusion, AVF creation leads to modified left and right ventricular function and increased peripheral flow, potentially mediated by cellular senescence and fibrosis, resulting in progressive cardiac remodeling. This model of uremic kidney disease can now be used to evaluate mechanisms of AVF induced cardiac disease and test the efficacy of therapeutics like senolytics and anti-fibrotic agents.