Citations

AbstractAimsAn artificial intelligence algorithm detecting age from 12-lead electrocardiogram (ECG) has been suggested to reflect ‘physiological age’. An increased physiological age has been associated with a higher risk of cardiac mortality in the non-transplant population. We aimed to investigate the utility of this algorithm in patients who underwent heart transplantation (HTx).Methods and resultsA total of 540 patients were studied. The average ECG ages within 1 year before and after HTx were used to represent pre- and post-HTx ECG ages. Major adverse cardiovascular event (MACE) was defined as any coronary revascularization, heart failure hospitalization, re-transplantation, and mortality. Recipient pre-transplant ECG age (mean 63 ± 11 years) correlated significantly with recipient chronological age (mean 49 ± 14 years, R = 0.63, P < 0.0001), while post-transplant ECG age (mean 54 ± 10 years) correlated with both the donor (mean 32 ± 13 years, R = 0.45, P < 0.0001) and the recipient ages (R = 0.38, P < 0.0001). During a median follow-up of 8.8 years, 307 patients experienced MACE. Patients with an increase in ECG age post-transplant showed an increased risk of MACE [hazard ratio (HR): 1.58, 95% confidence interval (CI): (1.24, 2.01), P = 0.0002], even after adjusting for potential confounders [HR: 1.58, 95% CI: (1.19, 2.10), P = 0.002].ConclusionElectrocardiogram age-derived cardiac ageing after transplantation is associated with a higher risk of MACE. This study suggests that physiological age change of the heart might be an important determinant of MACE risk post-HTx.

Abstract Aims Cardiovascular disease and cancer share common pathogenesis and risk factors. Coronary microvascular dysfunction (CMD), reflecting impaired coronary microvascular dilation in response to stress, is related to a higher risk of major cardiovascular events; however, its association with cancer has not been explored. Methods and results A retrospective study on 1042 patients with non-obstructive coronary artery diseases (NOCADs) was performed. Data regarding demographic, clinical history, diagnostic coronary reactivity test, and cancer occurrence were collected. Coronary microvascular dysfunction was defined as coronary flow reserve (the ratio of hyperaemic blood flow to resting blood flow) ≤2.5. Thirty-four per cent had CMD (67.4% female and the average age was 52.4 ± 12.2 years). Of 917 patients with no history of cancer, 15.5% developed cancer during follow-up [median of 9 (4, 16) years]. Kaplan–Meier analysis showed that CMD patients had lower cancer-free survival compared with those without CMD (log-rank P = 0.005). Cox proportional hazard analyses showed that after adjusting for age, sex, hypertension, diabetes, smoking, and glomerular filtration rate, CMD is independently associated with cancer [hazard ratio, 1.4; 95% confidence interval (CI), 1.09–2.04; P = 0.04]. The rate of major adverse cardiovascular events (MACE) was significantly higher in CMD patients compared with that in non-CMD patients who had a previous history of cancer [odds ratio (OR), 2.5; 95% CI, 1–6.2; P = 0.04] and those with no history of cancer (OR, 1.4; 95% CI, 1.01–1.9; P = 0.044). Conclusion Coronary microvascular dysfunction is associated with cancer incidence in patients presenting with NOCADs. This study emphasizes follow-up in patients with CMD to evaluate the risk of MACE as well as potential malignant diseases.

Introduction: Coronary vasomotor response is different between males and females. Overall, females have lower coronary flow reserve (CFR) than males due to higher baseline coronary flow than males. Hypothesis: Sex has an essential role in the interaction between age and CFR. Methods: We included 668 patients with nonobstructive coronary artery disease who underwent invasive coronary vasoreactivity testing using intracoronary incremental doses of adenosine (18-72 μg). Changes in CFR (hyperemic flow velocity/baseline flow velocity) with aging were separately analyzed between males (N=207, mean age 53±13 years) and females (N=461, mean age 54±12 years). We further divided patients by age of 53 which is average age of menopause. Results: In males, CFR decreased with aging in younger patients <53 years and tended to decrease in older male patients (all ages [N=207]: r=-0.33, P <0.0001; <53 years [N=99]: r=-0.27, P =0.01; ≥53 years [N=108]: r=-0.17, P =0.07) ( Figure A ). In contrast, CFR did not decrease with aging in younger females <53 years, whereas there was a significant negative correlation between CFR and age in older females ≥53 years (all ages [N=461]: r=-0.15, P =0.001; <53 years [N=211]: r=-0.006, P =0.39; ≥53 years [N=250]: r=-0.25, P <0.0001) ( Figure B ). Baseline microvascular resistance (BMR) was similar between younger and older males ( P =0.30), whereas older females had higher baseline BMR than younger females ( P <0.0001) ( Figure C ). Conclusions: CFR decreased with aging in males and older females, but not in younger females, potentially highlighting the role of protective hormonal differences in maintaining low baseline coronary tone in younger females.

Background Elevated plasma ceramides are independent predictors of cardiovascular disease and mortality in patients with advanced epicardial coronary artery disease. Our understanding of plasma ceramides in early epicardial coronary artery disease, however, remains limited. We examined the role of plasma ceramides in early coronary atherosclerosis characterized by coronary endothelial dysfunction. Methods and Results Participants presenting with chest pain and nonobstructive epicardial coronary artery disease underwent coronary endothelial function. Patients (n=90) demonstrated abnormal coronary endothelial function with acetylcholine (≥20% decrease in coronary artery diameter or ≤50% increase in coronary blood flow). A total of 30 controls had normal coronary endothelial function. Concentrations of plasma ceramide 18:0 ( P =0.038), 16:0 ( P =0.021), and 24:0 ( P =0.019) differed between participants with normal and abnormal coronary endothelial function. Ceramide 24:0 (odds ratio [OR], 2.23 [95% CI, 1.07–4.66]; P =0.033) and 16:0 (OR, 1.91×10 6 [95% CI, 11.93–3.07×10 11 ]; P =0.018) were independently associated with coronary endothelial dysfunction. Among participants with endothelium‐dependent coronary dysfunction (n=78), ceramides 16:0 (OR, 5.17×10 5 [95% CI, 2.83–9.44×10 10 ]; P =0.033), 24:0 (OR, 2.98 [95% CI, 1.27–7.00]; P =0.012), and 24:1/24:0 (OR, 4.39×10 −4 [95% CI, 4×10 −7 –0.48]; P =0.030) were more likely to be elevated. Conclusions The current study demonstrated an association between increased circulating ceramide levels and coronary endothelial dysfunction in the absence of epicardial coronary artery disease. This study supports the role of plasma ceramides as a potential biomarker or a therapeutic target for early coronary atherosclerosis in humans.

Background Pulse pressure (PP), a raw index of arterial stiffness, is inversely related to coronary microvascular function, even among patients with non-obstructive coronary artery disease (CAD), as per non-invasive studies. We aimed to determine whether invasive aortic PP is associated with coronary microvascular endothelial dysfunction (CMED) and/or coronary microvascular endothelial independent dysfunction (CMEID) in patients with non-obstructed CAD. Methods We retrospectively analysed a cohort of 1894 patients (mean age, 51.2 years; 1261 (66.6%) women) who presented with chest pain and non-obstructive CAD (angiographic stenosis <50%); coronary vasoreactivity was assessed in the mid-left anterior descending artery. The patients were classified based on whether aortic PP was high (≥50 mm Hg). CMEID was defined as abnormal coronary flow reserve (<2.5) or hyperaemic myocardial resistance (>2.0 mm Hg/cm/s), CMED was defined as abnormal acetylcholine-induced per cent change of coronary blood flow (≤50%). Results Patients with high aortic PP had a higher rate of CMEID than those with low aortic PP (40.9 vs 25.2%, p<0.001). Conversely, aortic PP was not associated with CMED. On multivariate analysis, high aortic PP was associated with CMEID occurrence (OR 1.42, 95% CI 1.13 to 1.78; p=0.003). On follow-up (median, 150 months), all-cause death was more frequent among patients with vs without high aortic PP (20.1% vs 7.3%, log-rank p<0.001) and HR was 2.08 (95% CI 1.34 to 3.32, p=0.002) on multivariate cox regression analysis. Furthermore, among patients with low aortic PP, CMEID was an independent risk factor for all-cause mortality (HR 2.04, 95% CI 1.01 to 4.16, p=0.048). Conclusion In patients with non-obstructive CAD, invasive aortic PP was significantly associated with CMEID, but not with CMED. High aortic PP was an independent predictor of all-cause mortality, but CMEID was an independent risk factor in patients with low aortic PP.

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.

AbstractBackgroundData regarding ventricular tachycardia (VT) or premature ventricular complex (PVC) ablation following mitral valve surgery (MVS) is limited. Catheter ablation (CA) can be challenging given perivalvular substrate in the setting of mitral annuloplasty or prosthetic valves.ObjectiveTo investigate the characteristics, safety, and outcomes of radiofrequency CA in patients with prior MVS and ventricular arrhythmias (VA).MethodsWe identified consecutive patients with prior MVS who underwent CA for VT or PVC between January 2013 and December 2018. We investigated the mechanism of arrhythmia, ablation approach, peri‐operative complications, and outcomes.ResultsIn our cohort, 31 patients (77% men, mean age 62.3 ± 10.8 years, left ventricular ejection fraction 39.2 ± 13.9%) with prior MVS underwent CA (16 VT; 15 PVC). Access to the left ventricle was via transseptal approach in 17 patients, and a retrograde aortic approach was used in 13 patients. A combined transseptal and retrograde aortic approach was used in one patient, and a percutaneous epicardial approach was combined with trans‐septal approach in one patient. Heterogenous scar regions were present in 94% of VT patients and scar‐related reentry was the dominant mechanism of VT. Forty‐seven percent of PVC patients had abnormal substrate at the site targeted for ablation. Clinical VA substrates involved the peri‐mitral area in six patients with VT and five patients with PVC ablation. No procedure‐related complications were reported. The overall recurrence‐free rate at 1‐year was 72.2%; 67% in the VT group and 78% in the PVC group. No arrhythmia‐related death was documented on long‐term follow‐up.ConclusionCA of VAs can be performed safely and effectively in patients with MVS.

Carotid plaque vulnerability features beyond the degree of stenosis may play a key role in the pathogenesis and recurrence of ischemic cerebrovascular events. This study sought to compare intraplaque hemorrhage (IPH) as a marker of plaque vulnerability in symptomatic patients with mild (<50%), moderate (50%–69%), and severe (≥70%) carotid artery stenosis. We included patients who experienced ischemic cerebrovascular events with no other identifiable sources and underwent carotid endarterectomy for mild (n=32), moderate (n=47), and severe (n=58) carotid artery stenosis. The degree of stenosis and imaging hallmarks were assessed by computed tomography angiography or magnetic resonance angiography. Plaque specimens were stained with hematoxylin and eosin and Movat pentachrome staining. Carotid plaques of patients with mild stenosis had a higher extent of IPH (%) on tissue analysis compared with patients with moderate (mild, 15.7% [interquartile range, 7.8%–26.7%]; moderate, 3.9% [0.0%–9.2%]; P <0.001) and severe carotid artery stenosis (mild, 15.7% [interquartile range, 7.8%–26.7%]; severe, 2.5% [interquartile range, 0.0%–11.2%]; P <0.001). When considering the degree of carotid artery stenosis as a continuous variable, a lower lumen narrowing was associated with higher extent of IPH ( P <0.001; R, −0.329). Our major finding is the association of IPH with mild carotid artery stenosis based on histological analysis. The current study may suggest that IPH potentially plays a role in the mechanism of stroke in patients with nonobstructive carotid stenosis.

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 &lt;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 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 (&lt;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) &lt;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