Publications

BACKGROUND: Identifying the cause of dyspnea (i.e., cardiac vs. non-cardiac) can be challenging in the absence of significant resting cardiac abnormalities. Exercise cardiovascular magnetic resonance (Ex-CMR) enables quantification of cardiac volumetric indices under physiological stress. Using Ex-CMR, we sought to develop a non-invasive imaging marker, referred to as the myocardial dynamic index (MDI), and to demonstrate its potential for evaluating cardiac dyspnea.

METHODS: MDI is a metric derived from Ex-CMR work-volume loop model that integrates rest and stress left ventricular (LV) end-diastolic and end-systolic volumes with workload measured during supine exercise, while accounting for body size and LV mass. To evaluate MDI as a marker of cardiac dyspnea, we retrospectively analyzed data from a prospective multicenter study measuring MDI in patients with cardiac or non-cardiac dyspnea. All had invasive exercise testing before Ex-CMR. Cardiac dyspnea was defined by established invasive and non-invasive criteria, including HFpEF (early to advanced) and HFmrEF. Non-cardiac dyspnea patients had normal invasive hemodynamics and cardiac function. Univariable and multivariable logistic regression identified clinical and imaging predictors of cardiac dyspnea. A base model incorporating clinical and rest CMR variables was compared to a model that included the base model plus MDI. Diagnostic performance was assessed using receiver operating characteristic analysis and compared using the DeLong test. MDI scan/re-scan reproducibility over one year, inter- and intra-observer reproducibility, and correlation with VO₂ max were evaluated.

RESULTS: Among 93 patients (66 with cardiac dyspnea, 27 with non-cardiac dyspnea), MDI was lower in patients with cardiac dyspnea (25.9±9.5 vs. 45.1±10.7 mL·W/g/m², p<0.0001). The base model included age, body mass index, NYHA class, and left atrial strain. In multivariable analysis, MDI emerged as the only independent predictor of cardiac dyspnea when added to the base model. Inclusion of MDI improved the AUC from 0.86 to 0.93 (p=0.012), while MDI alone yielded an AUC of 0.91. A strong correlation was observed between MDI and the VO₂ max index (r=0.84, p<0.0001). Reproducibility was excellent.

CONCLUSION: Ex-CMR MDI is independently associated with cardiac dyspnea and strongly correlates with the VO₂ max index. It aids in differentiating cardiac from non-cardiac dyspnea and provides incremental diagnostic value beyond conventional clinical and resting imaging parameters.

INTRODUCTION: Understanding how perceived interpersonal discrimination may affect women's cardiovascular health is key to informing prevention strategies, especially during mid-life when cardiovascular conditions emerge more frequently than in prior life stages.

METHODS: Participants are 451 women in Project Viva. In 2021-2022, participants completed the 9-item, race-neutral Williams Everyday Discrimination Scale (WEDS) via survey; total score ranged from 9 to 54, with higher scores indicating higher perceived discrimination. In 2022-2024, we collected in-person measures of body mass index (BMI), blood pressure and sleep duration (via actigraphy) and quality (via Patient-Reported Outcomes Measurement Information System sleep disturbance and sleep-related impairment forms). We defined obesity as BMI ≥30 kg/m2, hypertension as blood pressure ≥130/80 mm Hg or use of antihypertensive medications and short nightly sleep duration as sleep of <7 hours each night. We examined associations between WEDS (individual item and total scores) and cardiovascular outcomes using linear (continuous outcomes) or modified Poisson (binary outcomes) models.

RESULTS: At outcome measurement, women had a mean (SD) age of 55.8 (4.9) years and WEDS score of 14.9 (5.9); 74% self-identified as non-Hispanic White and 10% as non-Hispanic Black. After adjusting for age at outcome assessment, household income and education, a 10-point increment in total WEDS score was associated with a higher obesity risk (RR=1.40, 95% CI 1.10 to 1.79), higher BMI (β=1.62 kg/m2, 95% CI 0.50 to 2.74), shorter nightly sleep duration (β=-0.23 hours, 95% CI -0.41 to -0.06) and higher sleep disturbance (β=0.99, 95% CI -0.01 to 1.99) and sleep-related impairment t-scores (β=2.28, 95% CI 0.95 to 3.61). Most individual WEDS items were consistently associated with higher BMI and higher sleep impairment.

CONCLUSIONS: Higher perceived interpersonal discrimination was associated with higher BMI, risk of obesity, shorter sleep duration and poorer sleep quality among mid-life women. These findings underscore the association between interpersonal discrimination and cardiovascular health and highlight the importance of interventions aimed at reducing discrimination.

BACKGROUND: Physical inactivity is highly prevalent in heart failure (HF) and chronic obstructive pulmonary disease (COPD) and is associated with poor outcomes, including worsened quality of life, increased hospitalizations, readmissions, and mortality. Accessible interventions that improve physical activity are needed. Mind-body strategies are well-suited for promoting physical activity; they show promise for targeting key health behavior change processes.

OBJECTIVE: The aim of this study was to examine the feasibility and acceptability of a web-based pedometer-mediated mind-body intervention (Mindful Steps) for promoting walking among individuals with HF and COPD.

METHODS: In this pilot randomized controlled trial, participants with chronic, stable HF and COPD were randomized to Mindful Steps or usual care in a 2:1 ratio. Mindful Steps is a 12-month multimodal intervention that includes a pedometer with individualized step-count goals, live mind-body exercise (MBE) classes, and a web platform with mind-body videos, motivation messages, and educational tips. Feasibility (recruitment rate, retention), intervention acceptability, and intervention adherence were the primary outcomes. Exploratory outcomes assessed at baseline, 3-, 6-, 9-, and 12-months included daily step counts, cognitive-behavioral/psychosocial measures, health-related quality of life, and self-reported physical function. Participants were enrolled in the study from April 2019 to July 2021. The study was converted to all-digital during the pandemic after March 2020.

RESULTS: Forty-one participants were randomized to Mindful Steps (n=26) or usual care (n=15). The recruitment rate was 3% (43/178), and overall study retention was 76% (31/41). In the intervention group, over 12 months, 58% (15/26) met a predefined benchmark for MBE class adherence (attending >70% of classes). Participants engaged most consistently with the MBE classes, the pedometer, and mind-body videos. There was a positive signal regarding group differences in the change in daily step counts from baseline, favoring intervention at 3 months (estimate=2038.77 steps per day between groups, 95% CI 289.76-3788.77), 6 months (estimate=3031.45, 95% CI 1261.15-4801.74), and 9 months (estimate=2703.80, 95% CI 862.97-4544.62). There were also positive signals regarding group differences in the change from baseline favoring intervention in the following outcomes: emotional awareness (estimate=0.88, 95% CI 0.15-1.61) and body listening (estimate=1.16, 95% CI 0.25-2.07) at 3-months; internal motivation (estimate=1.03, 95% CI 0.01-2.04) and pressure/tension at 6-months (estimate=-1.59, 95% CI -2.55 to -0.63); and exercise self-efficacy at 12 months (estimate=1.77, 95% CI 0.20-3.33).

CONCLUSIONS: Mindful Steps was largely feasible, acceptable, and had adequate intervention engagement. There were positive signals favoring the multimodal web intervention for daily step counts, interoceptive awareness, internal motivation, and exercise self-efficacy that will inform hypotheses in future studies. A pivot to fully remote conduct during the pandemic was successful. A larger trial examining the efficacy of Mindful Steps for promoting physical activity is warranted.

TRIAL REGISTRATION: ClinicalTrials.gov NCT03003780; https://clinicaltrials.gov/study/NCT03003780.

Individuals with dementia have a heightened hip fracture and fall risk but whether markers of brain injury are associated with hip fracture and falls is unknown. We tested the hypothesis that higher circulating brain injury markers were associated with increased risk of hip fracture and fall hospitalizations. Brain injury markers were measured in 2141 participants (mean age 77.9 yr; 60% women). Brain injury markers included neurofilament light chain (NfL), a marker of axonal injury; glial fibrillary acidic protein (GFAP), a marker of astrocytic injury; total Tau, whose many functions include neuron microtubule stabilization; and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a major protein of neurons. Incident hip fractures and hospitalizations for falls were identified through participant report and confirmed with medical records or medicare claims. Hazard ratios were computed for a doubling exposure (log2 transformed brain injury marker) using multivariable-adjusted Cox models. After a median follow-up of 11 yr, 304 incident hip fractures and 284 incident fall hospitalizations occurred. Doubling of GFAP and NfL were associated with a 22% (p = .048) and 42% (p < .001) higher risk of hip fracture, respectively. Additional adjustment for cognitive function, gait speed, grip strength, inflammatory markers, and depressive symptoms had no effect on results. Models that adjusted for all 4 brain markers showed that only NfL was independent of the other markers. Neurofilament light chain was also associated with a 47% increase risk of hospitalization for falls. There was no association of total Tau or UCH-L1 with hip fracture or falls. GFAP was also unrelated to fall hospitalizations. Neurofilament light chain was independently associated with an incident risk of hip fracture and fall hospitalizations. These results suggest that subclinical degrees of brain injury may contribute to falls and hip fracture. Future research is needed to test whether the association between NfL and hip fracture is independent of falls.

Hypertensive disorders are a common complication of pregnancy, with secondary hypertension estimated to impact around 1% of pregnancies. There are numerous causes of secondary hypertension including chronic kidney disease, renal artery stenosis, primary aldosteronism, Cushing syndrome, pheochromocytomas, thyroid disorders, obstructive sleep apnea, coarctation of the aorta, and medication side effects. Identifying the underlying cause of hypertension in pregnancy is critical to determine the appropriate treatment. This review will focus on the pregnancy specific diagnosis and management considerations for secondary hypertension.

OBJECTIVE: Preeclampsia, a medical complication of pregnancy, is associated with central nervous system (CNS) signs and symptoms, such as headache, hyperexcitability, hyperreflexia, visual disturbances, and seizures (referred to as eclampsia). We hypothesized that markers of neurological injury such as plasma neurofilaments comprising light chains (NfL) and phosphorylated heavy chains (pNfH), would be elevated in preeclampsia and could serve as biomarkers of severity of preeclampsia.

STUDY DESIGN: We first tested NfL and pNfH in nested case-control study from a third trimester plasma bank from patients who delivered at the Beth Israel Deaconess Medical Center (Boston Cohort, N = 288). We then validated the NfL and pNfH alterations in an independent cohort of women who were evaluated for preeclampsia at another tertiary care hospital in South Chicago (Chicago Cohort, N = 393). Data are presented as median (interquartile range) or proportion, and logistic regression was used to estimate risk ratios (RR) and 95 % confidence intervals (CI).

RESULTS: In the Boston cohort, plasma NfL concentrations were 10.8 (8.2, 15.0) pg/ml in normotensive controls versus 15.9 (10.1, 24.8) in preeclampsia (p = 0.002). Likewise, pNfH concentrations were 92.1 (55.6, 148) pg/ml in controls versus 141.5 (93.9, 212.0) in preeclampsia, respectively (p = 0.0004). The adjusted odds ratio (OR) for the risk of preeclampsia in the highest tertile of control NfL and pNfH concentrations, compared with lowest quartiles, was 3.72 (1.70, 8.17) and 3.99 (1.77, 9.03). Similar findings were replicated in the primarily African-American Chicago cohort (OR for NfL: 4.36 [2.46, 7.70] and pNfH: 2.91 [1.66, 5.13]). The risk of preeclampsia with severe features was highest among women who were in the highest quartile of the control distributions for both biomarkers but not for either biomarker alone (adjusted OR for Boston and Chicago cohorts were 7.56 and 5.78 respectively).

CONCLUSION: Markers of neurological injury are markedly elevated in preeclampsia in Caucasians and African Americans. Prospective studies are needed to evaluate whether these markers could herald the onset of eclampsia.

BACKGROUND: Endovascular repair of large diameter infrarenal and complex abdominal aortic aneurysms has been associated with worse outcomes. Whether these associations also apply to thoracoabdominal aortic aneurysms (TAAAs) remains unclear.

METHODS: We identified all patients who underwent endovascular repair for intact TAAAs between July 2010 and July 2024 in the Vascular Quality Initiative. A TAAA was defined as having a proximal aneurysm extent between zones 2 and 6, with at least one renal or visceral artery treated. Locally estimated scatterplot smoothing curves were used to visualize the relationship between preoperative aneurysm diameter and perioperative mortality, which informed the sex-specific definition of large aneurysms. Aneurysm size was categorized based on maximum diameter as follows (females/males): large (>60 mm/>65 mm), small (<50 mm/<55 mm), and medium (50-60 mm/55-65 mm). Perioperative outcomes were assessed using logistic regression models, and 5-year mortality was evaluated using adjusted Kaplan-Meier methods and Cox regression. Both large and small aneurysms were compared with medium-sized aneurysms.

RESULTS: A total of 1309 patients were included; of these, 54% underwent repair for medium-sized aneurysms, 37% for large aneurysms, and 9.1% for small aneurysms. The median follow-up was 345 days. After adjustment, compared with medium-sized aneurysms, large aneurysms were associated with 31% higher odds of any perioperative complication (adjusted odds ratio, 1.31; 95% confidence interval, 1.00-1.72; P = .046) and nearly twice the hazard of 5-year mortality (adjusted hazard ratio, 1.94; 95% confidence interval, 1.43-2.62; P < .01). The odds of perioperative mortality and in-hospital reintervention were similar between medium-sized and large aneurysms. No significant differences in perioperative outcomes or 5-year mortality were observed between patients with small and medium-sized aneurysms.

CONCLUSIONS: After endovascular repair for TAAAs, compared with medium-sized aneurysms, large aneurysms (>60 mm in females, >65 mm in males) were associated with higher odds of any complication and higher 5-year mortality. Patients with small aneurysms (<50 mm in females, <55 mm in males) demonstrated similar perioperative outcomes and 5-year mortality compared with those with medium-sized aneurysms. These findings highlight the need to optimize management strategies for patients with large TAAAs and emphasize the importance of improved screening programs to enable earlier detection.

INTRODUCTION: Dementia has been strongly linked with cardiovascular disease, but the relationships between cardiovascular disease and brain health at subclinical stages have not been fully explored. We investigated the associations between subclinical cardiac dysfunction, defined by cardiac biomarkers and echocardiography, and novel neurobiomarkers associated with the brain injury in older adults.

METHODS: We included 962 participants from the Cardiovascular Health Study who had no history of stroke, transient ischemic attack, atrial fibrillation, heart failure, or myocardial infarction. We analyzed cross-sectional associations using linear regression. Outcomes variables were serum neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), two markers of subclinical brain injury. Exposure variables were serum N-terminal pro-brain-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) and subclinical cardiac measures including echocardiographic left atrial reservoir strain, left ventricular average longitudinal strain, early diastolic strain rate of the left ventricle, decreased left ventricular ejection fraction, average E/e', percent predicted left ventricular mass, and left atrial diameter.

RESULTS: Among 844 participants with serum biomarkers, hs-cTnT was significantly associated with NfL (β = 1.881, 95 % CI: (0.729, 3.032), p = 0.001), and this association remained significant even after mutual adjustment for NT-proBNP (β = 1.781, 95 % CI: (0.626, 2.937), p = 0.003). NT-proBNP was also associated with NfL (β = 1.170, 95 % CI: (0.047, 2.293), p = 0.041), although this association was slightly attenuated and not statistically significant after adjustment for hs-cTnT (β = 1.004, 95 % CI: (-0.119, 2.126), p = 0.08). There were no significant associations observed for either circulating marker with GFAP, nor were echocardiographic variables associated with NfL or GFAP.

CONCLUSIONS: In older adults without clinically identified cardiovascular disease, subclinical cardiac dysfunction identified through hs-cTnT and, to a lesser extent, NT-proBNP, was associated with higher levels of NfL, a marker of brain injury. This novel insight suggests that even subclinical cardiac disease is linked to brain health.

INTRODUCTION: Contrasting active treatment against a placebo has long been the gold standard in clinical medicine. The possible impact of placebo responses in surgery has recently been investigated using sham surgery. Despite indications that both genuine and placebo surgeries may lead to positive outcomes, no investigation into the differential routes to improvement has been performed.

OBJECTIVES: To assess the mechanisms involved in improvements seen in patients with sacroiliac joint pain who undergo genuine or placebo surgery.

METHODS: This randomized controlled trial incorporated both subjective and objective assessments, including functional magnetic resonance imaging and experimental pain testing, at baseline and 6-month follow-up in a surgical trial including patients with chronic pain. Twenty-three patients were randomized to receive genuine surgery (sacroiliac joint fusion) or placebo (sham). An additional 7 patients were included as observational controls.

RESULTS: There was a significant reduction in weekly pain intensity for both the genuine and placebo groups at follow-up, with greater reductions in the genuine group compared with placebo (P = 0.04). The difference was driven by a few "super-responders" in the genuine group. Clinical improvements correlated with experimental pain outcomes at the operated sacroiliac joint. Functional brain connectivity between the somatosensory cortex and the default mode network decreased more in the genuine group compared with the placebo group.

CONCLUSION: Preliminary findings indicate decreased connectivity between somatosensory and default mode networks for patients in the genuine vs sham group, demonstrating the first findings of differential neural processing in pain-relevant brain networks after genuine vs placebo surgery using objective measures. Understanding the active mechanisms of surgery may lead to personalized treatments, more effective pain reduction, and less side effects for patients with pain.