Citations

Abstract Background Coronary vasomotor response is different between males and females. However, the prognostic impact of this difference in coronary physiologic indices has not been characterized in patients with no obstructive coronary artery disease (NOCAD). Purpose We aimed to investigate the sex-specific differences of coronary vasomotor function in response to adenosine in a large cohort of patients with NOCAD and its impact on long-term clinical outcomes Methods We included 668 NOCAD patients who underwent invasive coronary vasoreactivity testing using intracoronary incremental doses of adenosine (18–72 μg) with available follow-up data. Indices of coronary vasomotor response were compared between males and females, and their prognostic impact on major adverse cardiovascular events (MACE: death, myocardial infarction, revascularization, and stroke) were analyzed based on sex. Results Females (N=461, mean age 54±12 years) had lower baseline microvascular resistance (BMR) and higher baseline average peak velocity (APV) than males (N=207, mean age 53±13 years), while hyperemic microvascular resistance (HMR) and hyperemic APV were similar between males and females. Consequently, coronary flow reserve (CFR: hyperemic/baseline APV) and resistive reserve ratio (RRR: BMR/HMR) were lower in females than males (Figure 1A). Lower CFR and RRR, as well as lower BMR and higher baseline APV were associated with MACE only in males, but not in females. Higher HMR was the only predictor for MACE in females (Figure 1B). Conclusions Sex-specific differences in coronary vasomotor response to adenosine may provide different prognostic values between males and females. Funding Acknowledgement Type of funding sources: None.

Abstract Aims The current gold standard comprehensive assessment of coronary microvascular dysfunction (CMD) is through a limited-access invasive catheterization lab procedure. We aimed to develop a point-of-care tool to assist clinical guidance in patients presenting with chest pain and/or an abnormal cardiac functional stress test and with non-obstructive coronary artery disease (NOCAD). Methods and results This study included 1893 NOCAD patients (<50% angiographic stenosis) who underwent CMD evaluation as well as an electrocardiogram (ECG) up to 1-year prior. Endothelial-independent CMD was defined by coronary flow reserve (CFR) ≤2.5 in response to intracoronary adenosine. Endothelial-dependent CMD was defined by a maximal percent increase in coronary blood flow (%ΔCBF) ≤50% in response to intracoronary acetylcholine infusion. We trained algorithms to distinguish between the following outcomes: CFR ≤2.5, %ΔCBF ≤50, and the combination of both. Two classes of algorithms were trained, one depending on ECG waveforms as input, and another using tabular clinical data. Mean age was 51 ± 12 years and 66% were females (n = 1257). Area under the curve values ranged from 0.49 to 0.67 for all the outcomes. The best performance in our analysis was for the outcome CFR ≤2.5 with clinical variables. Area under the curve and accuracy were 0.67% and 60%. When decreasing the threshold of positivity, sensitivity and negative predictive value increased to 92% and 90%, respectively, while specificity and positive predictive value decreased to 25% and 29%, respectively. Conclusion An artificial intelligence-enabled algorithm may be able to assist clinical guidance by ruling out CMD in patients presenting with chest pain and/or an abnormal functional stress test. This algorithm needs to be prospectively validated in different cohorts.

Background White matter hyperintensity (WMH), characterized by hyperintensities on T2‐weighted fluid‐attenuated inversion recovery brain magnetic resonance imaging, has been linked to an increased risk of ischemic stroke (IS). Endothelial dysfunction is an indicator of vascular dysfunction, predicting the risk of IS. This study aimed to investigate the association between endothelial dysfunction and regional WMH, and its impact on future risk of IS. Methods and Results We enrolled 219 patients (mean age, 53.1±14.1 years; 34.7% men) who underwent peripheral endothelial function assessment using reactive hyperemia peripheral arterial tonometry and brain magnetic resonance imaging without any history of IS. Volumetric WMH segmentation was automatically extrapolated using a validated automated digital tool. Total and juxtacortical WMH volume/intracranial volume (%) increased with aging and became more prominent in patients aged >50 years (n=131) than those aged ≤50 years (n=88) (total WMH: ≤50 years, Pearson r =0.24, P =0.03; >50 years, Pearson r =0.62, P <0.0001; juxtacortical WMH: ≤50 years, Pearson r =0.09, P =0.40; >50 years, Pearson r =0.55, P <0.0001). Reactive hyperemia peripheral arterial tonometry index was negatively associated with total and juxtacortical WMH volume/intracranial volume (%) in patients aged >50 years after adjustment for other covariates (reactive hyperemia peripheral arterial tonometry index, standardized β coefficient −0.17, P =0.04). Juxtacortical WMH volume/intracranial volume (%) was associated with an increased risk of IS during median follow‐up of 6.5 years (hazard ratio, 1.47; 95% CI, 1.05–1.92; P =0.03). Conclusions Peripheral endothelial dysfunction is associated with an increased volume of juxtacortical WMH in patients aged >50 years, which is a potential marker to predict future risk of IS.

Abstract Aims Cardiac allograft vasculopathy (CAV) is the major cause of increased morbidity and mortality after heart transplantation. Peripheral endothelial dysfunction (PED) is associated with early atherosclerosis and future risk of major adverse cardiovascular events (MACE) in non-heart transplant population. We aimed to investigate the association of PED with future MACE, and plaque progression assessed by intravascular ultrasound (IVUS) after heart transplantation. Methods and results We included 66 transplant patients who underwent serial IVUS surveillance for CAV and baseline assessment of peripheral endothelial function using reactive hyperaemia peripheral arterial tonometry. PED was defined as reactive hyperaemia index &lt; 2. The primary endpoint of the study was to investigate the association of PED with CAV progression assessed by intravascular ultrasound (IVUS). CAV progression was assessed as the change (Δ) in plaque volume divided by segment length, and Δ plaque index (plaque volume/vessel volume), adjusted for the time between IVUS measurements (median 3.0 [2.2, 3.1] years). The secondary endpoint was to investigate the association between PED and future MACE, which was defined as any incident of revascularization, heart failure hospitalization, stroke, myocardial infarction, re-transplantation, and death. Patients with PED (n = 27) had more yearly plaque progression (0.50 ± 0.66 vs. 0.15 ± 0.50 mm3/mm/year, P = 0.02) and a higher Δ plaque index (2.41 ± 2.53% vs. 0.69 ± 2.22%, P = 0.01). Patients with PED were more likely to experience MACE during a median follow-up of 8.2 years (interquartile range [7.6, 8.4]), after adjustment for potential cofounders such as age, high-density lipoprotein cholesterol levels, total rejection score, baseline International Society for Heart & Lung Transplantation CAV grade, and indication of transplantation. (hazard ratio 2.15, 95% confidence interval [1.09, 4.23], P = 0.03). Conclusions Peripheral endothelial dysfunction is associated with increased plaque progression and adverse long-term cardiovascular outcomes in transplant patients. PED assessment might be a useful clinical tool for risk stratification after heart transplantation.

Background Anxiety disorders are the most prevalent mental disorders and are an emerging risk factor for coronary artery disease and its complications. We determine the relationship between having a clinical diagnosis of an anxiety disorder and coronary endothelial dysfunction (CED) using invasive coronary reactivity testing across both sexes. Methods and Results Patients presenting with chest pain and nonobstructive coronary artery disease (stenosis <40%) at coronary angiography underwent an invasive assessment of CED. Patients were categorized as having a clinical diagnosis of an anxiety disorder at the time of coronary angiography by chart review. The frequency of CED was compared between patients with versus without an anxiety disorder and after stratifying patients by sex. Between 1992 and 2020, 1974 patients (mean age, 51.3 years; 66.2% women) underwent invasive coronary reactivity testing, of which 550 (27.9%) had a documented anxiety disorder at the time of angiography. There was a significantly higher proportion of patients with any type of CED in those with an anxiety disorder in all patients (343 [62.7%] versus 790 [56.4%]; P =0.011) that persisted in women but not in men. After adjusting for covariables, anxiety was significantly associated with any CED among all patients (odds ratio [95% CI], 1.36 [1.10–1.68]; P =0.004), and after stratifying by sex in women but not in men. Conclusions Anxiety disorders are significantly associated with CED in women presenting with chest pain and nonobstructive coronary artery disease. Thus, CED may represent a mechanism underpinning the association between anxiety disorders and coronary artery disease and its complications, highlighting the role of anxiety as a potential therapeutic target to prevent cardiovascular events.

Abstract Background: Primary sclerosing cholangitis (PSC) is a rare, chronic cholestatic liver disease that often progresses to end-stage liver disease and/or the development of hepatobiliary neoplasia. Lack of prognostic tools and treatment options for PSC is driven in part by our poor understanding of its pathogenesis, which is thought to be complex, the interaction of genetic variants, environmental influences and biological response throughout the course of disease. The PSC Scientific Community Resource (PSC-SCR) seeks to overcome previous shortcomings by facilitating novel research in PSC with the ultimate goals of individualizing patient care and improving patient outcomes.Methods: PSC patients who receive their health care at Mayo Clinic or a collaborating site are identified by chart review and invited in person or by mail to participate. Non-Mayo patients are offered enrollment if they provide sufficient access to their medical records to evaluate inclusion/exclusion criteria. Controls without liver disease are identified with assistance of the Mayo Clinic Biobank. Participant consent is obtained at the beginning of the recruitment process by mail-in, electronic or face-to-face protocols. Clinical data is extracted from the medical record by qualified physicians and entered in a custom designed database. Participants fill out a custom-designed, comprehensive questionnaire, which collects scientifically relevant demographic and clinical information. Biospecimens are collected using mail-in kitsthar are returned via overnight carrier service and processed by the biospecimen accessioning and processing facility at Mayo Clinic, which coordinates sample transfers and provides required sample preparation services.The resource is currently being utilized to perform omics-scale projects investigating the exposome, metabolome, methylome, immunome and microbiome in PSC. Datasets and residual biospecimens will be shared with researchers proposing scientifically sound PSC-focused research with approval of the appropriate review boards.Discussion:Patient-based studies leveraging the latest technologies for targeted and wide-scale interrogation of multiple omics layers offer promise to accelerate PSC research through discovery of unappreciated aspects of disease pathogenesis. However, the rarity of PSC severely limits such studies. Here we describe our effort to overcome this limitation, the PSC-SCR, a repository of patient biospecimens coupled with clinical and omics data for use by the broader PSC research community.

Abstract Aims Circulating progenitor cells (CPCs) play a role in vascular repair and plaque stability, while osteocalcin (OC) expressing CPCs have been linked to unstable plaque and adverse cardiovascular outcomes. However, their role in cardiac allograft vasculopathy (CAV) has not been elucidated. This cohort study aimed to investigate the contribution of CPCs on CAV progression and cardiovascular events after heart transplantation. Methods and results A total of 80 heart transplant patients (mean age 55 ± 14 years, 72% male) undergoing annual intravascular ultrasound (IVUS) had fresh CPCs marked by CD34, CD133, and OC counted in peripheral blood using flow cytometry, on the same day as baseline IVUS. CAV progression was assessed by IVUS as the change (Δ) in plaque volume divided by segment length (PV/SL), adjusted for the time between IVUS measurements [median 3.0, interquartile range (2.8–3.1) years] and was defined as ΔPV/SL that is above the median ΔPV/SL of study population. Major adverse cardiac events (MACEs) were defined as any incident of revascularization, myocardial infarction, heart failure admission, re-transplantation, stroke, and death. Patients with higher CD34+CD133+ CPCs had a decreased risk of CAV progression [odds ratio 0.58, 95% confidence interval (CI) (0.37–0.92), P = 0.01] and MACE [hazard ratio (HR) 0.79, 95% CI (0.66–0.99), P = 0.05] during a median (interquartile range) follow-up of 8.0 years (7.2–8.3). Contrarily, higher OC+ cell counts were associated with an increased risk of MACE [HR 1.26, 95% CI (1.03–1.57), P = 0.02]. Conclusions Lower levels of CD34+CD133+ CPCs are associated with plaque progression and adverse long-term outcomes in patients who underwent allograft heart transplantation. In contrast, higher circulating OC+ levels are associated with adverse long-term outcomes. Thus, CPCs might play a role in amelioration of transplant vasculopathy, while OC expression by these cells might play a role in progression.

Background Resistive reserve ratio (RRR), or the ratio of baseline to hyperemic microvascular resistance, has prognostic implications in predicting clinical outcomes in patients with obstructive coronary artery disease. However, its value in patients with angina or ischemia with nonobstructive coronary artery disease is unknown. Methods and Results We included 1692 patients with nonobstructive coronary artery disease who underwent invasive coronary vasoreactivity testing. Abnormal coronary flow reserve (CFR, the ratio of hyperemic and baseline resting flow velocities) and RRR were defined as <2.5 and <2.62, respectively. The mortality rate was marginally higher in patients with abnormal CFR (428 patients [25%]) than those with normal CFR (38 [9%] versus 81 [6%]; P =0.08), and was significantly higher in patients with abnormal RRR (716 patients [42%]) than those with normal RRR (70 [10%] versus 49 [5%], P =0.0002) over the median follow‐up of 11.3 years. Patients with abnormal CFR had marginally lower survival than those with normal CFR (log‐rank P =0.08). In contrast, patients with abnormal RRR had significantly lower survival than those with normal RRR (log‐rank P =0.001). Abnormal RRR was associated with shorter time to death even after adjustment for other covariates (adjusted hazard ratio, 1.63; 95% CI, 1.11–2.38; P =0.01). Conclusions In patients with no obstructive coronary artery disease, RRR was superior to CFR in predicting long‐term survival. An RRR <2.62 was associated with 1.6 times increased risk of death in patients with nonobstructive coronary artery disease. Indices of coronary microcirculatory resistive reserve comprising flow‐ and pressure‐derived values may reflect underlying microvascular pathology more faithfully than flow‐alone indices like CFR.

Introduction: Cardiac allograft vasculopathy (CAV) is a major determinant of long term graft survival. Endothelial progenitor cells (EPC) expressing osteocalcin (OC) have been linked to atherosclerosis. However, little is known regarding bone-forming osteoblast-lineage (OL) cells, and their role in atherosclerosis and CAV. Methods: Heart transplant patients undergoing serial Intravascular Ultrasound (IVUS) and progenitor cell studies were included in the study. OL cells, defined as cells positive for alkaline phosphatase (AP) and OC, were counted using flow cytometry on the day of baseline IVUS. A follow up IVUS was done 3 years later. Gray-scale and virtual-histology IVUS were used to evaluate vessel size, plaque burden, and plaque composition (fibrous, fibrofatty, necrotic core, calcified). Patients were divided into two groups by the median change (Δ) in necrotic core volume and plaque volume over 3 years. Results: A total of 55 patients (mean age 52±15 years, 65% males) were included. At baseline, median time after transplant was 4.2 years. Average vessel area at baseline and three years were 15.8 ±4.6 and 15.3 ±5.4 mm2, respectively (p=0.32). However, 24/55 patients (44%) had positive remodeling. The number of OL cells was positively correlated with Δvessel (r=0.36, p=0.01) and Δlumen areas. (r=0.30, p=0.02). Patients with greater Δplaque volume and Δnecrotic core volume had higher OL cell levels compared to those with below medians (Δplaque volume: 95 [30,348] vs. 30 [10, 90] OL per 100,000 counts, p=0.01; Δnecrotic core volume: 95 [22.5, 320] vs. 30 [10, 90] OL per 100,000 counts, p=0.03) (Fig. 1A and 1B). Conclusions: The number of OL cells in heart transplant patients correlates with positive vascular remodeling, accompanied by increased lumen area over 3 months. Furthermore, patients with unstable plaque features had higher OL cells, suggesting a possible role in pathologic plaque progression.