Christopher L. Schaich

Introduction Norepinephrine remains first-line vasopressor therapy for septic shock despite its association at high doses with undesirable cardiovascular, kidney, and immune effects. Angiotensin-II (Ang-II) is a non-catecholamine vasopressor of the renin-angiotensin-aldosterone system (RAAS) now approved to increase blood pressure in vasodilatory shock. RAAS dysregulation is common in septic shock and may represent a treatable trait. However, few prospective investigations evaluate the effect of early Ang-II use in septic shock on dysfunctional RAAS biology, host-response, or clinical outcomes. Therefore, we designed a mechanistic clinical trial to test the hypothesis that early Ang-II therapy in septic shock normalizes systemic RAAS abnormalities and modulates innate immune responses. Methods and Analysis The Mechanistic Assessment of Norepinephrine TheRapy vs. Angiotensin-II in Septic Shock (MANTRA) trial is an investigator-initiated, prospective, multicenter, open-label, randomized mechanistic clinical trial. Adults with septic shock by Sepsis-3 criteria receiving a norepinephrine-equivalent dose (NED) of 0.10-0.50 mcg/kg/min will be randomized 1:1 to primary Ang-II (to a maximum of 40 ng/kg/min) or norepinephrine (to a maximum 35 mcg/min) treatment strategies over a 48-hour period. The primary outcome is the between-group difference in plasma renin trajectory from baseline to 24 hours, analyzed using a linear mixed-effects model with a treatment-by-time interaction term. With n=78, the trial has 90% power (at two-sided α=0.05) to detect a 25% between-group difference in 24-hour renin. Secondary clinical outcomes include longitudinal NED, hours alive and vasopressor-free at 72 hours, a 28-day composite outcome (days alive and free of vasopressors, renal replacement therapy, and mechanical ventilation), treatment failure requiring crossover or protocol discontinuation, and thrombotic and arrhythmia events through 28 days. Secondary mechanistic outcomes include serial RAAS biomarkers (prorenin, soluble prorenin receptor, angiotensinogen, ACE, ACE2, Ang-II, angiotensin-(1-7), aldosterone, and DPP3), immune measures (ex vivo monocyte function, monocyte gene expression, plasma cytokines), and organ injury biomarkers. Enrollment is planned from 5/2026-7/2030. Strengths and limitations of this study MANTRA is a randomized trial comparing angiotensin-II against an active standard-of-care norepinephrine strategy rather than placebo, enrolling patients earlier in septic shock than prior trials restricted to catecholamine-resistant shock. Serial sampling profiles RAAS peptides, innate immune function, and organ-injury biomarkers, which will generate rich mechanistic data on how vasopressor strategy shapes the host response. The sample size is adequate for the biomarker primary endpoints and will establish feasibility for a larger trial, but it does not provide sufficient power for hard clinical endpoints, which remain exploratory. MANTRA compares two open-label vasopressor strategies rather than monotherapies; clinician retain discretion over background and rescue vasopressors, steroids, and crossover, which may attenuate differences between-arms. The 48-hour intervention window limit inference about clinician-assessed outcomes and the durability of treatment effect.

Background: Insulin resistance (IR) and lipoprotein(a), Lp(a), are established contributors to cardiovascular disease (CVD) risk. Whether IR modifies the association between Lp(a) and CVD in primary prevention remains uncertain. Methods: This prospective cohort study included UK Biobank participants without baseline CVD. IR at enrollment was assessed using the triglyceride‐glucose index (TyG). The primary outcome was first major adverse cardiovascular event, defined as peripheral arterial disease, coronary artery disease, myocardial infarction, ischemic stroke, or cardiovascular death. Cox models estimated adjusted hazard ratios (aHRs) with 95% CIs for log‐transformed Lp(a) and TyG, adjusting for each other. Lp(a) was categorized as P ‐value for the multiplicative interaction between TyG and Lp(a) was 0.07. Relative to reference, aHRs (95% CI) were 1.15 (1.10–1.20) for ≥125/low IR, 1.09 (1.06–1.12) for <125/high IR, and 1.32 (1.24–1.41) for ≥125/high IR. Conclusions: Lp(a) and IR each independently contribute to cardiovascular risk, with a combination offering improved risk stratification. This suggests that accounting for IR may enhance the assessment of Lp(a)‐associated risk in the context of primary CVD prevention setting.

Aims: Circulating ketone bodies (KB) are an important source of metabolic fuel for the myocardium under physiological and pathological conditions. Prior studies have linked KB levels with adverse cardiovascular outcomes. However, their relationship with atrial fibrillation (AF) risk remains unknown. The objective is to evaluate the association of KB levels with the risk of incident AF. Methods and results: This prospective, multicentre cohort study recruited patients without baseline AF from the Multi-Ethnic Study of Atherosclerosis (MESA) and the UK Biobank (UKB), respectively. Total KB levels were measured by nuclear magnetic resonance spectroscopy in both studies. The associations between total and individual KB and incident AF were evaluated using multivariable-adjusted Cox proportional hazard models. Prespecified interaction analyses were performed for smoking status, history of diabetes mellitus, history of hypertension, body mass index, and self-reported race/ethnicity (to represent a social construct). A total of 6783 participants [mean (standard deviation, SD) age 62 (10) years, 52% women, 38% White, 27.5% Black, 21.8% Hispanic, and 11.6% Chinese American] from MESA and 116 480 participants [mean (SD) age 56.5 (8) years, 54% women, 94% White] from the UKB were included. Over a median follow-up of 16.5 (10.3–17.4) years in MESA and 13.6 (12.8–14.4) years in the UKB, higher levels of total KB were associated with a higher risk of incident AF. In MESA, each doubling of baseline total KB levels was associated with a 1.08-fold increased hazard of incident AF on follow-up [95% confidence interval (CI): 1.00–1.16] after adjustment for confounding factors. Consistent results were obtained in a subgroup analysis stratified by different types of KB (β-hydroxybutyrate, acetoacetate, and acetone). There was a significant interaction with current smoking, such that per doubling of total KB levels was associated with a 1.32-fold increased hazard for incident AF in current smokers (95% CI: 1.08–1.61), but this association was not seen among former/never smokers [hazard ratio (95% CI): 1.05 (0.95–1.13)]. These results were replicated in the UKB. Conclusion: Higher concentrations of KB are associated with an increased risk of AF in predominantly healthy, community-based cohorts, acknowledging that many participants also had comorbidities such as hypertension and diabetes, particularly among smokers. Ketone bodies could serve as a potential biomarker for identifying populations at risk for AF.

Background: High right ventricular pacing burden can result in pacing‐induced cardiomyopathy (PICM). The goal of this study was to investigate whether angiotensin‐converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and β‐blockers (BB) are associated with a reduction in risk of PICM in patients with high right ventricular pacing burden. Methods: This was a single‐center, retrospective study that included patients with normal ejection fraction and complete heart block who underwent pacemaker implantation. The medical therapy group included patients who received ACEI/ARB, BB, or both. The control group received neither ACEI/ARB nor BB. The primary end point was PICM, defined as upgrade to a biventricular device or reduction in ejection fraction to ≤40% without another cause identified. Fine‐Gray subdistribution hazard models were used to determine the relationship between medical therapy and cumulative incidence of PICM. Results: The study included 642 patients (mean±SD age, 71±14 years; 51% women). Over 10 years of follow‐up, 76 (11.8%) received ACEI/ARB only; 49 (7.6%) received BB only, and 86 (13.4%) received both. PICM occurred in 10 of 211 in the medical therapy group (4.7%) and in 30 of 431 in the control group (7.0%). In adjusted weighted analyses, the risk of PICM was significantly lower in the medical therapy group compared with the control group (hazard ratio [HR], 0.59 [95% CI, 0.45–0.77]). Patients on combination therapy had the lowest risk (HR, 0.46 [95% CI, 0.31–0.69]). Conclusions: Patients with high right ventricular pacing burden who received ACEI, ARB, or BB within 10 years of pacemaker implantation had a lower incidence of PICM.

BACKGROUND: To estimate the association of degree of prematurity with arterial stiffness in young adults using augmentation index corrected for a heart rate of 75 beats per minute (AIx@75) and pulse wave velocity (PWV). METHODS: This was a secondary cross-sectional analysis from a prospective cohort study of young adults born preterm with extremely low or very low birth weight (<1,500 g) and term-born peers with normal birth weight. Gestational age at birth was the exposure. Arterial stiffness outcome assessment was performed using radial artery tonometry (Sphygmocor) and a pressure wave transducer with an electrocardiogram (Colin). We used directed acyclic graph-informed multivariable linear regression to estimate the association of gestational age at birth on the continuous and binary scales with AIx@75 and PWV. RESULTS: Of the 113 participants, 110 had AIx data and 97 had PWV data for analysis. AIx@75 was 5.07% higher in the preterm group. In adjusted analysis, each one-week higher gestational age at birth was associated with lower AIx@75 among the entire cohort (−0.38% per week, 95% confidence interval −0.74, −0.02). There was no statistically significant difference in PWV between the preterm and term groups. CONCLUSIONS: There was a higher AIx in young adults with increasing severity of prematurity amongst the entire cohort, but no difference in PWV. More studies are needed that directly assess the severity of prematurity with arterial wall stiffness and alterations in arterial wall structure to determine if they are associated with a higher risk of hypertension and cardiovascular disease long term in the premature population.

Background: The association between atrial fibrillation (AF) and dementia and cognitive decline in individuals with hypertension is not well established. Methods: The Systolic Blood Pressure Intervention Trial (SPRINT) enrolled participants with hypertension at high risk of cardiovascular disease (CVD) but without diabetes or a history of stroke. Participants with baseline pre-existing clinical dementia, prescribed dementia medications, or missing AF or cognition data were excluded. AF was identified using centrally read electrocardiograms. Mild cognitive impairment (MCI) and probable dementia (PD) were determined during follow-up by an adjudication committee. Multivariable Cox proportional hazards regression models were employed to assess the association of time-dependent AF with MCI, PD, and a composite endpoint of MCI/PDI. Results: A total of 8539 participants (mean age: 67.9 years; 35.1% female) were included in the analysis. Of these, 264 had AF at baseline or during follow-up. Over a median follow-up period of 5 years, 318 PD, 625 MCI, and 849 composite PD or MCI events occurred. In models adjusted for treatment assignment, baseline sociodemographics, CVD risk factors, and potential confounders, time-dependent AF was associated with incident PD, MCI, and a composite endpoint of MCI/PDI [HR (95% CI): 1.84 (1.09, 3.13), 1.59 (1.01, 2.53), and 1.63 (1.12, 2.38), respectively]. Further adjustment for incident stroke did not significantly change these associations. Conclusions: AF is associated with an increased risk of dementia and cognitive impairment in patients with hypertension but not diabetes or stroke. Further research is needed to determine whether AF management strategies can mitigate cognitive decline.

We measured circulating components of the renin-angiotensin system (RAS) longitudinally over 5 days among patients hospitalized with COVID-19 and new-onset hypoxemia. We found that higher serum angiotensin-converting enzyme (ACE)-2 protein and ACE2/ACE ratio, both at baseline and when analyzed as time-varying, repeated measures, were associated with lower 90-day mortality. Results suggest a role for circulating ACE2 as a biomarker of adverse outcomes and could inform treatment strategies targeting the RAS in severe COVID-19 illness.

BACKGROUND: Intensive blood pressure (BP) control in youth with chronic kidney disease (CKD) slows progression, delaying the need for kidney replacement therapy (KRT). Most youth with CKD have hypertension and BP control is difficult to achieve outside of controlled experimental settings. Implementing effective BP control strategies in this population may be cost-saving despite requiring additional resources. Our objective was to determine the economic and clinical impact of intensive versus usual care for BP management in youth with CKD in a microeconomic model. METHODS: We developed a decision tree from the US payer perspective to estimate the total costs and clinical effect of an intensified BP intervention over 5 years, modeled after the ESCAPE trial (Effect of Strict Blood Pressure Control and Angiotensin-Converting Enzyme [ACE] Inhibition on Progression of Chronic Renal Failure in Pediatric Patients) protocol. We compared this intervention to usual care in a hypothetical population of youth with mild-to-moderate CKD. Probabilities were informed by published literature; cost estimates were informed by publicly available data. Our outcomes were the net discounted cost of an intensive BP intervention, number needed to treat with the intervention to prevent 1 KRT episode, and incremental cost per KRT episode avoided. RESULTS: An intensive BP intervention, with a goal of an average 24-hour mean arterial pressure <50th percentile, improved outcomes with net cost savings of $9440 per participant over 5 years compared with usual care. To prevent 1 episode of KRT over 5 years, 13 participants need to receive intensive BP intervention. CONCLUSIONS: Routine use of the ESCAPE protocol for intensive BP control in youth with CKD could save overall costs for the payer and improve clinical outcomes.