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Background: Coronary endothelial dysfunction (CED) causes angina/ischemia in patients with nonobstructive coronary artery disease (NOCAD). Patients with CED have decreased number and function of CD34+ cells involved in normal vascular repair with microcirculatory regenerative potential and paracrine anti-inflammatory effects. We evaluated safety and potential efficacy of intracoronary autologous CD34+ cell therapy for CED. Methods: Twenty NOCAD patients with invasively diagnosed CED and persistent angina despite maximally tolerated medical therapy underwent baseline exercise stress test, GCSF (granulocyte colony stimulating factor)-mediated CD34+ cell mobilization, leukapheresis, and selective 1×10 5 CD34+ cells/kg infusion into left anterior descending. Invasive CED evaluation and exercise stress test were repeated 6 months after cell infusion. Primary end points were safety and effect of intracoronary autologous CD34+ cell therapy on CED at 6 months of follow-up. Secondary end points were change in Canadian Cardiovascular Society angina class, as-needed sublingual nitroglycerin use/day, Seattle Angina Questionnaire scores, and exercise time at 6 months. Change in CED was compared with that of 51 historic control NOCAD patients treated with maximally tolerated medical therapy alone. Results: Mean age was 52±13 years; 75% were women. No death, myocardial infarction, or stroke occurred. Intracoronary CD34+ cell infusion improved microvascular CED (%acetylcholine-mediated coronary blood flow increased from 7.2 [−18.0 to 32.4] to 57.6 [16.3–98.3]%; P =0.014), decreased Canadian Cardiovascular Society angina class (3.7±0.5 to 1.7±0.9, Wilcoxon signed-rank test, P =0.00018), and sublingual nitroglycerin use/day (1 [0.4–3.5] to 0 [0–1], Wilcoxon signed-rank test, P =0.00047), and improved all Seattle Angina Questionnaire scores with no significant change in exercise time at 6 months of follow-up. Historic control patients had no significant change in CED. Conclusions: A single intracoronary autologous CD34+ cell infusion was safe and may potentially be an effective disease-modifying therapy for microvascular CED in humans. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03471611.

Abstract Background A higher serum phosphorus level, although within the normal range has been linked to coronary artery and aortic calcification in the non-transplant population. Coronary calcification is mostly associated with donor-derived lesions, and is uncommon within the first years after heart transplantation. Purpose We aimed to investigate the association of phosphorus levels with plaque calcification after heart transplantation. Methods A total of 156 patients who underwent virtual histology intravascular ultrasound (VH-IVUS) studies for cardiac allograft vasculopathy (CAV) surveillance and had fasting serum phosphorus levels <4.5 mg/dL, were included in the analyses. IVUS analyses were performed in the proximal left anterior descending artery, and plaque composition of dense calcium (DC) was evaluated using VH-IVUS, and presented as percent DC of total plaque volume. The patients were separated into 3 groups according to tertiles of serum phosphorus levels. Results Mean recipient and donor ages were 54±13 and 31±14 years, respectively. Mean serum phosphorus in recipients was 3.5±0.6 mg/dL, with median time after transplantation at the IVUS studies of 6 (3,10) years. There were no significant differences in %DC between phosphorus tertiles in patients who underwent IVUS within 6 years after transplantation (p=0.11, Fig. 1A). However, beyond 6 years after transplantation, we observed an incremental association between phosphorus levels and the extent of calcification (p=0.02, Fig. 1B). In this group, serum phosphorus levels significantly correlated with %DC (standardized β=0.29, P=0.008), and this correlation remained significant after adjustment for donor age, recipient age, and eGFR (standardized β=0.26, P=0.001). Conclusion Higher serum phosphorus levels were associated with a level-dependent increase in calcified coronary artery plaque in patients starting 6 years post heart transplant. Long-term exposure to higher serum phosphorus, even within the normal range, might promote plaque calcification after heart transplantation. Funding Acknowledgement Type of funding sources: None.

Abstract Background An artificial intelligence (AI) algorithm detecting age from 12-lead ECG has been suggested to signal “physiological age” of the individual. Importantly, increased physiological age gauged by an increased difference between ECG-age and chronological age has been associated with higher risk of cardiac events in non-transplant population. Purpose We sought to investigate the validity of the AI-derived ECG-age algorithm in patients who underwent heart transplantation and its relationship to major adverse cardiovascular events (MACE). Methods A total of 489 consecutive patients who had undergone heart transplantation in our institution between 1994 and 2018 were studied. AI-ECG age was calculated by a previously-trained artificial intelligence (AI) algorithm using a 12-lead ECG per patient. ECGs used in the training process of the algorithm were excluded. The average of the ECG-ages within one year before and one year after heart transplantation was used to represent pre- and post-transplant ECG-ages. MACE was defined as any incidence of revascularization, re-transplantation, and death. Results Pre-transplant ECG-age (mean 63±10 years) correlated significantly with recipient chronological age (mean 50±13 years, r=0.57, p<0.0001), but this correlation between recipient and ECG-ages was weakened after transplantation (mean post-transplant ECG age of 55±10 years, r=0.34, p<0.0001). Interestingly, post-transplant ECG-age correlated significantly with donor age (mean ECG age of 55±10 years vs. mean donor age of 32±13 years, r=0.42, p<0.0001). During a median (IQR) follow-up of 9 (5, 14) years, 251 patients had MACE. Mean change in ECG age after transplantation compared to before was −8.8±12.7 years. Patients who had an increase in ECG-age after compared to before transplantation showed increased risk of MACE (HR: 1.53 [1.16, 2.01], p=0.002), independent of recipient and donor ages (adjusted HR: 1.68 [1.26, 2.25], p=0.001); whereas there were no significant differences in risk of MACE in patients who were transplanted with an older donor heart (HR: 1.07 [0.77, 1.50], p=0.66). In a Kaplan Meier survival analysis, those with increased ECG-age after transplantation had significantly lower MACE-free survival compared to those with decreased ECG-age. (Log-rank P=0.002; Wilcoxon P=0.001) (Figure) Conclusion Post-transplant ECG-age correlates more faithfully with the donor's than the recipient's chronological age, suggesting that ECG-age more closely reflects cardiac age than the patient age. Furthermore, ECG-age derived cardiac aging after transplantation is associated with higher risk of MACE. Funding Acknowledgement Type of funding sources: None.

Abstract Background Coronary microvascular dysfunction (CMD) is associated with an increased risk of cardiovascular morbidity and mortality. The current gold-standard comprehensive assessment of CMD is through a limited-access invasive catheterization lab procedure. Purposes We aimed to develop a point-of-care tool to assist clinical guidance in patients presenting with chest pain and/or an abnormal functional stress test and with non-obstructive coronary artery disease (NOCAD) based on demographic data and resting ECG waveforms. Methods This study included 1,893 NOCAD patients (<50% angiographic stenosis) who underwent CMD evaluation as well as a standard ECG up to 1 year prior. Microvascular endothelial-independent dysfunction was defined by abnormal coronary flow reserve (CFR) <2.5 in response to intracoronary adenosine administration. Microvascular endothelial dysfunction 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 style clinical data. The optimal classification threshold was determined by maximizing Youden's J. Results Mean age was 51±12 years and 66% were females (n=1,257). AUC 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 via logistic regression on tabular variables. AUC and accuracy were 0.67 and 60%; while sensitivity and NPV were 70% and 85%. Specificity and PPV were 56% and 0.35%. When decreasing the threshold from the “optimal” one (24%) to 15%, sensitivity and NPV increased to 92% and 90% respectively, while specificity and PPV decreased to 25% and 29% respectively (Figure 2). Conclusion An AI-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. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The James Nutter Family & Maria Long Family Fellowship in Cardiovascular Research and Mayo Clinic Figure 1Figure 2

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.

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 < 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.

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.