Patients With Coronary Microvascular Dysfunction Have Less Circulating α-Klotho.

BACKGROUND: Coronary microvascular dysfunction (CMD) represents an early functional characteristic of coronary vascular aging. Klotho (α-klotho) is a circulating protein inversely linked to physiological aging. We examined low klotho as a potential marker for vascular aging in patients with CMD and no coronary artery disease. METHODS AND RESULTS: Patients undergoing nonurgent angiogram for chest pain who had no coronary artery disease underwent invasive coronary microvascular and endothelial function testing. CMD was defined by ≤50% increase in coronary blood flow (percentage change in coronary blood flow) in response to intracoronary acetylcholine or coronary flow reserve ≤2. Fresh arterial whole blood was used to analyze circulating endothelial progenitor cells with flow cytometry. Stored arterial plasma was used for klotho analysis by ELISA. Participants with CMD (n=62) were compared with those without CMD (n=36). Those with CMD were age 55±10 years (versus 51±11 years; P=0.07) and 73% women (versus 81%; P=0.38). Traditional risk factors for coronary artery disease were similar between groups. Patients with CMD had less klotho (0.88±1.50 versus 1.75±2.38 ng/mL; P=0.03), and the odds of low klotho in CMD were significant in a logistic regression model after adjusting for traditional cardiovascular risk factors (odds ratio [OR], 0.80 [95% CI, 0.636-0.996]; P=0.05). Higher klotho was associated with higher numbers of endothelial progenitor cells with vascular regenerative potential (CD34+ and CD34+CD133+KDR+). Among a subgroup of patients with atherosclerotic cardiovascular disease risk <5% (n=58), CMD remained associated with lower klotho (OR, 0.80 [95% CI, 0.636-0.996]; P=0.047). CONCLUSIONS: Klotho may be a biomarker for CMD and may be a therapeutic target for groups of patients without significant traditional cardiovascular risk.

Predictive Value of Artificial Intelligence-Enabled Electrocardiography in Patients With Takotsubo Cardiomyopathy.

BACKGROUND: Recent studies have indicated high rates of future major adverse cardiovascular events in patients with Takotsubo cardiomyopathy (TC), but there is no well-established tool for risk stratification. This study sought to evaluate the prognostic value of several artificial intelligence-augmented ECG (AI-ECG) algorithms in patients with TC. METHODS AND RESULTS: This study examined consecutive patients in the prospective and observational Mayo Clinic Takotsubo syndrome registry. Several previously validated AI-ECG algorithms were used for the estimation of ECG- age, probability of low ejection fraction, and probability of atrial fibrillation. Multivariable models were constructed to evaluate the association of AI-ECG and other clinical characteristics with major adverse cardiac events, defined as cardiovascular death, recurrence of TC, nonfatal myocardial infarction, hospitalization for congestive heart failure, and stroke. In the final analysis, 305 patients with TC were studied over a median follow-up of 4.8 years. Patients with future major adverse cardiac events were more likely to be older, have a history of hypertension, congestive heart failure, worse renal function, as well as high-risk AI-ECG findings compared with those without. Multivariable Cox proportional hazards analysis indicated that the presence of 2 or 3 high-risk findings detected by AI-ECG remained a significant predictor of major adverse cardiac events in patients with TC after adjustment by conventional risk factors (hazard ratio, 4.419 [95% CI, 1.833-10.66], P=0.001). CONCLUSIONS: The combined use of AI-ECG algorithms derived from a single 12-lead ECG might detect subtle underlying patterns associated with worse outcomes in patients with TC. This approach might be beneficial for stratifying high-risk patients with TC.

Coronary Vasomotor Dysfunction Is Associated With Cardiovascular Events in Patients With Nonobstructive Coronary Artery Disease.

BACKGROUND: Coronary vasomotor dysfunction (CVDys) can be comprehensively classified on the basis of anatomy and functional mechanisms. OBJECTIVES: The aim of this study was to evaluate the association between different CVDys phenotypes and outcomes in patients with angina and nonobstructive coronary artery disease (ANOCA). METHODS: Patients with ANOCA who underwent coronary reactivity testing using an intracoronary Doppler guidewire to assess microvascular and epicardial coronary endothelium-dependent and endothelium-independent function were enrolled. Endothelium-dependent microvascular and epicardial coronary dysfunction were defined as a <50% change in coronary blood flow in response to intracoronary acetylcholine (Ach) infusion and a <-20% change in coronary artery diameter in response to Ach. Endothelium-independent microvascular and epicardial coronary dysfunction were defined as coronary flow reserve < 2.5 during adenosine-induced hyperemia and change in cross-sectional area in response to intracoronary nitroglycerin administration < 20%. Major adverse cardiac and cerebrovascular events (cardiovascular death, nonfatal MI, heart failure, stroke, and late revascularization) served as clinical outcomes. RESULTS: Among the 1,196 patients with ANOCA, the prevalence of CVDys was 24.5% and 51.8% among those with endothelium-independent and endothelium-dependent microvascular dysfunction, respectively, and 47.4% and 25.4% among those with endothelium-independent and endothelium-dependent epicardial coronary dysfunction, respectively. During 6.3 years (Q1-Q3: 2.5-12.9 years) of follow-up, patients with endothelium-dependent microvascular dysfunction, endothelium-dependent epicardial coronary dysfunction, or endothelium-independent microvascular dysfunction showed significantly higher event rates compared with those without (19.5% vs 12.0% [P < 0.001], 19.7% vs 14.6% [P = 0.038] and 22.2% vs 13.8% [P = 0.001], respectively). Coronary flow reserve (HR: 0.757; 95% CI: 0.604-0.957) and percentage change in coronary blood flow in response to Ach infusion (HR: 0.998; 95% CI: 0.996-0.999) remained significant predictors of major adverse cardiac and cerebrovascular event after adjustment for conventional risk factors. CONCLUSIONS: CVDys phenotype is differentially associated with worse outcomes, and endothelium-dependent and endothelium-independent microvascular function provide independent prognostic information in patients with ANOCA.

A novel method that can be used in both the diagnosis and treatment of peripheral arterial disease in diabetics: vibration-mediated dilation.

OBJECTIVE: The growing incidence of diabetes and the increasing life expectancy of the diabetic population worldwide has increased the number of diabetic vascular complications occurring in cardiology practice. As current treatment and prevention methods are less effective in this patient group, there is a need for new treatment methods in this area. Exercise, which reduces metabolic and vascular problems associated with diabetes, often becomes impossible, especially in advanced-stage patients who need exercise the most. Since exercise and flow-mediated dilation (FMD) are effective by stimulating mechanotransduction mechanisms on the endothelium, it can be expected that the same mechanisms could also be stimulated by direct vibration. METHODS: In order to test this hypothesis, in this study, a group of 20 type 2 diabetes patients (11 males, age 56.80 ± 11.05 years and diagnosed for 15.35 ± 8.61 years) were examined via the application of FMD and vibration-mediated dilation (VMD). We performed vibration for five minutes with 20-Hz frequency and 3-mm vertical amplitude, to the same side forearm, with a 30-minute interval. Using a 10-MHz linear echo probe, brachial artery diameter and flow velocities were recorded for 10 minutes before and at two-minute intervals after the FMD and VMD applications. Then brachial artery flow and resistance were calculated at each stage. RESULTS: In the first minute after FMD and VMD applications, brachial artery diameter and flow velocities increased significantly, and vascular resistance decreased significantly. None of the corresponding FMD or VMD parameters in the first minute was different. The artery diameters in the first minute after FMD and VMD were increased by 6.04 ± 5.29 and 5.49 ± 5.21%, respectively. At the tenth minute, these values decreased to 1.73 ± 3.21 and 2.05 ± 3.31%. In the FMD series, all parameters except brachial artery diameter returned to their baseline values after the fourth minute. After VMD, all parameters also decreased after the first minute, but the recovery was much slower. At each stage after the first minute, the VMD averages were higher than the baseline value and their corresponding FMD values. CONCLUSION: The results of this study indicated that vibration may be a powerful, long-lasting and feasible treatment option in patients with peripheral perfusion failure, developed due to diabetic macro- and microvascular complications.

Prognostic implications of unrecognized myocardial infarction and periprocedural myocardial injury on cardiac magnetic resonance imaging in patients with chronic coronary syndrome.

This study sought to evaluate the prognostic implications of the presence of preprocedural unrecognized myocardial infarction (UMI) and periprocedural myocardial injury (PMI) evaluated by delayed gadolinium enhancement cardiac magnetic resonance (DE-CMR) in patients with chronic coronary syndrome (CCS) undergoing elective percutaneous coronary intervention (PCI). We enrolled 250 CCS patients scheduled for elective PCI. UMI was defined as the presence of late gadolinium enhancement (LGE) detected by pre-PCI CMR in the region without medical history of revascularization and/or MI. Periprocedural new occurrence or increased volume of LGE in the target territory detected by post-PCI CMR (PPL) were used to assess PMI. In the final analysis of 235 patients, UMI and PPL were detected in 43 patients (18.3%) and 45 patients (19.1%), respectively. During follow-up for a median of 2.2 years, major adverse cardiac events (MACE) occurred in 31 (13.2%) patients. On multivariable analysis, UMI and PPL remained as significant predictors of MACE after adjusting confounding factors (HR 4.62, 95% CI 2.24-9.54, P < 0.001, HR 2.33, 95% CI 1.11-4.91, P = 0.026). In patients with CCS who underwent elective PCI, UMI and PPL were independent predictors of worse outcomes. UMI and PPL on DE-CMR might provide additional potential insight for the risk stratification of patients undergoing elective PCI.

Coronary microcirculation in nonculprit vessel territory in reperfused acute myocardial infarction.

BACKGROUND: There is an ongoing debate on the extension of reperfusion-related microvascular damage (MVD) throughout the remote noninfarcted myocardial regions in patients with ST-elevation myocardial infarction (STEMI) that undergo primary percutaneous intervention (pPCI). The aim of this study was to elucidate the impact of reperfusion on remote microcirculatory territory by analyzing hemodynamic alterations in the nonculprit-vessel in relation to reperfusion. METHODS: A total of 20 patients with STEMI undergoing pPCI were included. Peri-reperfusion temporal changes in hemodynamic parameters were obtained in angiographically normal nonculprit vessels before and 1-h after reopening of the culprit vessel. Intracoronary pressure and flow velocity data were compared using pairwise analyses (before and 1-h after reperfusion). RESULTS: In the non-culprit vessel, compared to the pre-reperfusion state, mean resting average peak velocity (33.4 ± 9.4 to 25.0 ± 4.9 cm/s, P < 0.001) and mean hyperemic average peak velocity (53.5 ± 14.4 to 42.1 ± 10.66 cm/s, P = 0.001) significantly decreased; whereas baseline (3.2 ± 1.0 to 4.0 ± 1.0 mmHg.cm-1.s, P < 0.001) and hyperemic microvascular resistance (HMR) (1.9 ± 0.6 to 2.4 ± 0.7 mmHg.cm-1.s, P < 0.001) and mean zero flow pressure (Pzf) values (32.5 ± 6.9 to 37.6 ± 8.3 mmHg, P = 0.003) significantly increased 1-h after reperfusion. In particular, the magnitude of changes in HMR and Pzf values following reperfusion were more prominent in patients with larger infarct size and with higher extent of MVD in the culprit vessel territory. CONCLUSION: Reperfusion-related microvascular injury extends to involve remote myocardial territory in relation to the magnitude of the adjacent infarction and infarct-zone MVD. (GUARD Clinical TrialsNCT02732080).

Circulating Progenitor Cells Are Associated With Bioprosthetic Aortic Valve Deterioration: A Preliminary Study.

Background Mechanisms underlying bioprosthetic valve deterioration are multifactorial and incompletely elucidated. Reparative circulating progenitor cells, and conversely calcification-associated osteocalcin expressing circulating progenitor cells, have been linked to native aortic valve deterioration. However, their role in bioprosthetic valve deterioration remains elusive. This study sought to evaluate the contribution of different subpopulations of circulating progenitor cells in bioprosthetic valve deterioration. Methods and Results This single-center prospective study enrolled 121 patients who had peripheral blood mononuclear cells isolated before bioprosthetic aortic valve replacement and had an echocardiographic follow-up ≥2 years after the procedure. Using flow cytometry, fresh peripheral blood mononuclear cells were analyzed for the surface markers CD34, CD133, and osteocalcin. Bioprosthetic valve deterioration was evaluated by hemodynamic valve deterioration (HVD) using echocardiography, which was defined as an elevated mean transprosthetic gradient ≥30 mm Hg or at least moderate intraprosthetic regurgitation. Sixteen patients (13.2%) developed HVD during follow-up for a median of 5.9 years. Patients with HVD showed significantly lower levels of reparative CD34+CD133+ cells and higher levels of osteocalcin-positive cells than those without HVD (CD34+CD133+ cells: 125 [80, 210] versus 270 [130, 420], P=0.002; osteocalcin-positive cells: 3060 [523, 5528] versus 670 [180, 1930], P=0.005 respectively). Decreased level of CD34+CD133+ cells was a significant predictor of HVD (hazard ratio, 0.995 [95% CI, 0.990%-0.999%]). Conclusions Circulating levels of CD34+CD133+ cells and osteocalcin-positive cells were significantly associated with the subsequent occurrence of HVD in patients undergoing bioprosthetic aortic valve replacement. Circulating progenitor cells might play a vital role in the mechanism, risk stratification, and a potential therapeutic target for patients with bioprosthetic valve deterioration.

Invasive aortic pulse pressure is linked to cardiac allograft vasculopathy after heart transplantation.

BACKGROUND: Pulse pressure (PP) has been linked to an increased risk of extent of coronary atherosclerosis and cardiovascular events. This study aimed to investigate the contribution of aortic PP on cardiac allograft vasculopathy (CAV) progression, and cardiovascular events after heart transplantation (HTx). METHODS: A total of 330 HTx patients (mean age 49 ± 25 years, 70.0% male) undergoing routine serial coronary intravascular ultrasound (IVUS) studies and had invasive aortic PP were enrolled. The median time from HTx to first IVUS was 13.6 months. CAV progression was assessed by IVUS as the changes (Δ) in plaque volume divided by the segment length (PV/SL), adjusted for the time between IVUS (median, 3.99 years; interquartile range, 1.99-7.20 years), and was defined as ΔPV/SL ≥0.50 mm3/mm/year. Major adverse cardiovascular event (MACE) was defined as any incidence of mortality, myocardial infarction, coronary revascularization, heart failure hospitalization, or re-transplantation. RESULTS: Recipient age, recipient sex, and renal dysfunction were independent determinant of high aortic PP (≥ 50 mmHg). High aortic PP was an independent determinant of CAV progression [odds ratio, 1.72; 95% confidence interval (CI), 1.01-2.93; p = 0.045]. Both high aortic PP (HR 1.46, 95% CI 1.01-2.11, p = 0.044) and high baseline CAV grade on angiogram (≥1, HR 1.50, 95% CI 1.03-2.21, p = 0.037) were independently associated with MACEs over 12 years. CONCLUSION: In post-HTx patients, high aortic PP was significantly associated with plaque progression. Both aortic PP and CAV grade are independently associated with MACE during long-term follow-up. These findings suggest that arterial stiffness and CAV can be important predictors of MACEs.

Electrocardiogram-Artificial Intelligence and Immune-Mediated Necrotizing Myopathy: Predicting Left Ventricular Dysfunction and Clinical Outcomes.

Objective: To characterize the utility of an existing electrocardiogram (ECG)-artificial intelligence (AI) algorithm of left ventricular dysfunction (LVD) in immune-mediated necrotizing myopathy (IMNM). Patients and Methods: A retrospective cohort observational study was conducted within our tertiary-care neuromuscular clinic for patients with IMNM meeting European Neuromuscular Centre diagnostic criteria (January 1, 2000, to December 31, 2020). A validated AI algorithm using 12-lead standard ECGs to detect LVD was applied. The output was presented as a percent probability of LVD. Electrocardiograms before and while on immunotherapy were reviewed. The LVD-predicted probability scores were compared with echocardiograms, immunotherapy treatment response, and mortality. Results: The ECG-AI algorithm had acceptable accuracy in LVD prediction in 74% (68 of 89) of patients with IMNM with available echocardiograms (discrimination threshold, 0.74; 95% CI, 0.6-0.87). This translates into a sensitivity of 80.0% and specificity of 62.8% to detect LVD. Best cutoff probability prediction was 7 times more likely to have LVD (odds ratio, 6.75; 95% CI, 2.11-21.51; P=.001). Early detection occurred in 18% (16 of 89) of patients who initially had normal echocardiograms and were without cardiorespiratory symptoms, of which 6 subsequently advanced to LVD cardiorespiratory failure. The LVD probability scores improved for patients on immunotherapy (median slope, -3.96; R = -0.12; P=.002). Mortality risk was 7 times greater with abnormal LVD probability scores (hazard ratio, 7.33; 95% CI, 1.63-32.88; P=.009). Conclusion: In IMNM, an AI-ECG algorithm assists detection of LVD, enhancing the decision to advance to echocardiogram testing, while also informing on mortality risk, which is important in the decision of immunotherapy escalation and monitoring.

Gradual Versus Abrupt Reperfusion During Primary Percutaneous Coronary Interventions in ST-Segment-Elevation Myocardial Infarction (GUARD).

Background Intramyocardial edema and hemorrhage are key pathological mechanisms in the development of reperfusion-related microvascular damage in ST-segment-elevation myocardial infarction. These processes may be facilitated by abrupt restoration of intracoronary pressure and flow triggered by primary percutaneous coronary intervention. We investigated whether pressure-controlled reperfusion via gradual reopening of the infarct-related artery may limit microvascular injury in patients undergoing primary percutaneous coronary intervention. Methods and Results A total of 83 patients with ST-segment-elevation myocardial infarction were assessed for eligibility and 53 who did not meet inclusion criteria were excluded. The remaining 30 patients with totally occluded infarct-related artery were randomized to the pressure-controlled reperfusion with delayed stenting (PCRDS) group (n=15) or standard primary percutaneous coronary intervention with immediate stenting (IS) group (n=15) (intention-to-treat population). Data from 5 patients in each arm were unsuitable to be included in the final analysis. Finally, 20 patients undergoing primary percutaneous coronary intervention who were randomly assigned to either IS (n=10) or PCRDS (n=10) were included. In the PCRDS arm, a 1.5-mm balloon was used to achieve initial reperfusion with thrombolysis in myocardial infarction grade 3 flow and, subsequently, to control distal intracoronary pressure over a 30-minute monitoring period (MP) until stenting was performed. In both study groups, continuous assessment of coronary hemodynamics with intracoronary pressure and Doppler flow velocity was performed, with a final measurement of zero flow pressure (primary end point of the study) at the end of a 60-minute MP. There were no complications associated with IS or PCRDS. PCRDS effectively led to lower distal intracoronary pressures than IS over 30 minutes after reperfusion (71.2±9.37 mm Hg versus 90.13±12.09 mm Hg, P=0.001). Significant differences were noted between study arms in the microcirculatory response over MP. Microvascular perfusion progressively deteriorated in the IS group and at the end of MP, and hyperemic microvascular resistance was significantly higher in the IS arm as compared with the PCDRS arm (2.83±0.56 mm Hg.s.cm-1 versus 1.83±0.53 mm Hg.s.cm-1, P=0.001). The primary end point (zero flow pressure) was significantly lower in the PCRDS group than in the IS group (41.46±17.85 mm Hg versus 76.87±21.34 mm Hg, P=0.001). In the whole study group (n=20), reperfusion pressures measured at predefined stages in the early reperfusion period showed robust associations with zero flow pressure values measured at the end of the 1-hour MP (immediately after reperfusion: r=0.782, P<0.001; at the 10th minute: r=0.796, P<0.001; and at the 20th minute: r=0.702, P=0.001) and peak creatine kinase MB level (immediately after reperfusion: r=0.653, P=0.002; at the 10th minute: r=0.597, P=0.007; and at the 20th minute: r=0.538, P=0.017). Enzymatic myocardial infarction size was lower in the PCRDS group than in the IS group with peak troponin T (5395±2991 ng/mL versus 8874±1927 ng/mL, P=0.006) and creatine kinase MB (163.6±93.4 IU/L versus 542.2±227.4 IU/L, P<0.001). Conclusions In patients with ST-segment-elevation myocardial infarction, pressure-controlled reperfusion of the culprit vessel by means of gradual reopening of the occluded infarct-related artery (PCRDS) led to better-preserved coronary microvascular integrity and smaller myocardial infarction size, without an increase in procedural complications, compared with IS. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02732080.

Impact of invasive aortic pulse pressure on coronary microvascular endothelial-independent dysfunction and on mortality in non-obstructive coronary artery disease.

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.

Circulating progenitor cells are associated with plaque progression and long-term outcomes in heart transplant patients.

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.

Carotid Plaques From Symptomatic Patients With Mild Stenosis Is Associated With Intraplaque Hemorrhage.

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.

Artificial intelligence-derived cardiac ageing is associated with cardiac events post-heart transplantation.

Aims: An 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 results: A 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]. Conclusion: Electrocardiogram 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.

Impact of Peripheral Microvascular Endothelial Dysfunction on White Matter Hyperintensity.

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 ß 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.

Peripheral microvascular dysfunction is associated with plaque progression and adverse long-term outcomes in heart transplant patients.

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.

Compositional change of gut microbiome and osteocalcin expressing endothelial progenitor cells in patients with coronary artery disease.

Osteogenic endothelial progenitor cells (EPCs) contribute to impaired endothelial repair and promote coronary artery disease (CAD) and vascular calcification. Immature EPCs expressing osteocalcin (OCN) has been linked to unstable CAD; however, phenotypic regulation of OCN-expressing EPCs is not understood. We hypothesized that gut-microbiome derived pro-inflammatory substance, trimethylamine N-oxide (TMAO) might be associated with mobilization of OCN-expressing EPCs. This study aimed to investigate the association between dysbiosis, TMAO, and circulating mature and immature OCN-expressing EPCs levels in patients with and without CAD. We included 202 patients (CAD N = 88; no CAD N = 114) who underwent assessment of EPCs using flow cytometry and gut microbiome composition. Mature and immature EPCs co-staining for OCN were identified using cell surface markers as CD34+/CD133-/kinase insert domain receptor (KDR)+ and CD34-/CD133+/KDR+ cells, respectively. The number of observed operational taxonomy units (OTU), index of microbial richness, was used to identify patients with dysbiosis. The number of immature OCN-expressing EPCs were higher in patients with CAD or dysbiosis than patients without. TMAO levels were not associated with circulating levels of OCN-expressing EPCs. The relative abundance of Ruminococcus gnavus was moderately correlated with circulating levels of immature OCN-expressing EPCs, especially in diabetic patients. Gut dysbiosis was associated with increased levels of TMAO, immature OCN-expressing EPCs, and CAD. The relative abundance of Ruminococcus gnavus was correlated with immature OCN-expressing EPCs, suggesting that the harmful effects of immature OCN-expressing EPCs on CAD and potentially vascular calcification might be mediated by gut microbiome-derived systemic inflammation.

Vascular Aging Detected by Peripheral Endothelial Dysfunction Is Associated With ECG-Derived Physiological Aging.

Background An artificial intelligence algorithm that detects age using the 12-lead ECG has been suggested to signal "physiologic age." This study aimed to investigate the association of peripheral microvascular endothelial function (PMEF) as an index of vascular aging, with accelerated physiologic aging gauged by ECG-derived artificial intelligence-estimated age. Methods and Results This study included 531 patients who underwent ECG and a noninvasive PMEF assessment using reactive hyperemia peripheral arterial tonometry. Abnormal PMEF was defined as reactive hyperemia peripheral arterial tonometry index ≤2.0. Accelerated or delayed physiologic aging was calculated by the Δ age (ECG-derived artificial intelligence-estimated age minus chronological age), and the association between Δ age and PMEF as well as its impact on composite major adverse cardiovascular events were investigated. Δ age was higher in patients with abnormal PMEF than in patients with normal PMEF (2.3±7.8 versus 0.5±7.7 years; P=0.01). Reactive hyperemia peripheral arterial tonometry index was negatively associated with Δ age after adjustment for cardiovascular risk factors (standardized ß coefficient, -0.08; P=0.048). The highest quartile of Δ age was associated with an increased risk of major adverse cardiovascular events compared with the first quartile of Δ age in patients with abnormal PMEF, even after adjustment for cardiovascular risk factors (hazard ratio, 4.72; 95% CI, 1.24-17.91; P=0.02). Conclusions Vascular aging detected by endothelial function is associated with accelerated physiologic aging, as assessed by the artificial intelligence-ECG Δ age. Patients with endothelial dysfunction and the highest quartile of accelerated physiologic aging have a marked increase in risk for cardiovascular events.