Ticagrelor Enhances the Cardioprotective Effects of Ischemic Preconditioning in Stable Patients Undergoing Percutaneous Coronary Intervention: the TAPER-S Randomized Study.

BACKGROUND: Ticagrelor improves clinical outcomes in patients with acute coronary syndrome compared with clopidogrel. Ticagrelor also inhibits cell uptake of adenosine and has been associated with cardioprotective effects in animal models. We sought to investigate the potential cardioprotective effects of ticagrelor, as compared with clopidogrel, in stable patients undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: This was a Prospective Randomized Open Blinded End-points (PROBE) trial enrolling stable patients with coronary artery disease (CAD) requiring fractional flow reserve (FFR)-guided PCI of intermediate epicardial coronary lesions. ST-segment elevation at intracoronary (IC)-ECG during a two-step sequential coronary balloon inflations in the reference vessel during PCI was used as an indirect marker of cardioprotection induced by ischemic preconditioning. The primary endpoint of the study was the comparison of the delta (Δ) (difference) ST-segment elevation measured by intracoronary-ECG during two-step sequential coronary balloon inflations. RESULTS: Fifty-three patients were randomized to either clopidogrel or ticagrelor. The study was stopped earlier because the primary endpoint was met at a pre-specified interim analysis. ΔST-segment elevation was significantly higher in ticagrelor as compared to clopidogrel arms (p<0.0001). Ticagrelor was associated with lower angina score during coronary balloon inflations. There was no difference in coronary microvascular resistance between groups. Adenosine serum concentrations were increased in patients treated with ticagrelor as compared to those treated with clopidogrel. CONCLUSIONS: Ticagrelor enhances the cardioprotective effects of ischemic preconditioning compared with clopidogrel in stable patients with CAD undergoing PCI. Further studies are warranted to fully elucidate the mechanisms through which ticagrelor may exert cardioprotective effects in humans. Clinical Trial Registration: http://www.clinicaltrials.gov. Unique Identifier: NCT02701140.

Individual Lesion-Level Meta-Analysis Comparing Various Doses of Intracoronary Bolus Injection of Adenosine With Intravenous Administration of Adenosine for Fractional Flow Reserve Assessment.

BACKGROUND: Intravenous infusion of adenosine is considered standard practice for fractional flow reserve (FFR) assessment but is associated with adverse side-effects and is time-consuming. Intracoronary bolus injection of adenosine is better tolerated by patients, cheaper, and less time-consuming. However, current literature remains fragmented and modestly sized regarding the equivalence of intracoronary versus intravenous adenosine. We aim to investigate the relationship between intracoronary adenosine and intravenous adenosine to determine FFR. METHODS: We performed a lesion-level meta-analysis to compare intracoronary adenosine with intravenous adenosine (140 µg/kg per minute) for FFR assessment. The search was conducted in accordance to the Preferred Reporting for Systematic Reviews and Meta-Analysis statement. Lesion-level data were obtained by contacting the respective authors or by digitization of scatterplots using custom-made software. Intracoronary adenosine dose was defined as; low: <40 µg, intermediate: 40 to 99 µg, and high: ≥100 µg. RESULTS: We collected 1972 FFR measurements (1413 lesions) comparing intracoronary with intravenous adenosine from 16 studies. There was a strong correlation (correlation coefficient =0.915; P<0.001) between intracoronary-FFR and intravenous-FFR. Mean FFR was 0.81±0.11 for intracoronary adenosine and 0.81±0.11 for intravenous adenosine (P<0.001). We documented a nonclinically relevant mean difference of 0.006 (limits of agreement: -0.066 to 0.078) between the methods. When stratified by the intracoronary adenosine dose, mean differences between intracoronary and intravenous-FFR amounted to 0.004, 0.011, or 0.000 FFR units for low-dose, intermediate-dose, and high-dose intracoronary adenosine, respectively. CONCLUSIONS: The present study documents clinically irrelevant differences in FFR values obtained with intracoronary versus intravenous adenosine. Intracoronary adenosine hence confers a practical and patient-friendly alternative for intravenous adenosine for FFR assessment.

Clinical, angiographic and echocardiographic correlates of epicardial and microvascular spasm in patients with myocardial ischaemia and non-obstructive coronary arteries.

BACKGROUND: Coronary vasomotor dysfunction represents an important mechanism responsible for myocardial ischaemia in patients with non-obstructive coronary artery disease (CAD). The use of invasive provocative tests allows identifying patients with epicardial or microvascular spasm. Of note, clinical characteristics associated with the occurrence of epicardial or microvascular spasm have still not completely clarified. METHODS AND RESULTS: We prospectively enrolled consecutive patients undergoing coronary angiography for suspected myocardial ischaemia/necrosis with evidence of non-obstructive CAD and undergoing intracoronary provocative test for suspected vasomotor dysfunction. Patients with a positive provocative test were enrolled. Clinical, echocardiographic and angiographic characteristics of patients were evaluated according to the pattern of vasomotor dysfunction (epicardial vs. microvascular spasm). We included 120 patients [68 patients with stable angina and 52 patients with myocardial infarction and non-obstructive coronary arteries (MINOCA)]. In particular, 77 (64.2%) patients had a provocative test positive for epicardial spasm and 43 (35.8%) patients for microvascular spasm. Patients with epicardial spasm were more frequently males, smokers, had higher rates of diffuse coronary atherosclerosis at angiography and more frequently presented with MINOCA. On the other hand, patients with microvascular spasm presented more frequently diastolic dysfunction. At multivariate logistic regression analysis male sex, smoking, and diffuse coronary atherosclerosis were independent predictors for the occurrence of epicardial spasm. CONCLUSIONS: Our study showed that specific clinical features are associated with different responses to intracoronary provocative test. Epicardial spasm is more frequent in males and in MINOCA patients, whereas microvascular spasm is more frequent in patients with stable angina and is associated with diastolic dysfunction.

The Influence of Aortic Valve Obstruction on the Hyperemic Intracoronary Physiology: Difference Between Resting Pd/Pa and FFR in Aortic Stenosis.

The reliability of fractional flow reserve (FFR) in aortic stenosis (AS) has been questioned because of the uncertain response to vasodilators. A retrospective multicenter cohort of 114 AS patients who underwent coronary physiology assessment was compared with 154 controls before and after propensity matching adjustment. The difference between resting distal coronary vs aortic pressure ratio (Pd/Pa) and FFR (ΔPd/Pa-FFR) was tested against the severity of AS. ΔPd/Pa-FFR was not influenced by the severity of AS in terms of aortic valve area (r = - 0.02, p = 0.83) and gradient (r = - 0.05, p = 0.64) or by the left ventricle hypertrophy (r = - 0.03, p = 0.88). Conversely, ΔPd/Pa-FFR was influenced by the presence of diabetes (r = - 0.24, p = 0.005), peripheral vascular disease (r = - 0.16, p = 0.047), and chronic kidney disease (r = - 0.19, p = 0.03). No significant difference was observed in the ΔPd/Pa-FFR between patients with AS and matched controls. Further studies are warranted to validate the FFR-guided revascularization in patients with AS.

Frequency-domain optical coherence tomography plaque morphology in stable coronary artery disease: sex differences.

BACKGROUND: The cause for discrepancy in the clinical presentation and outcome of coronary artery disease (CAD) between men and women is not established. Different prevalences of risk factors or specific sex-related atherosclerotic aspects have been advocated as possible explanations. We investigated coronary plaque morphology looking at possible differences in plaque vulnerability between men and women with stable CAD. PATIENTS AND METHODS: We retrospectively collected and analyzed clinical data and coronary plaque morphology by frequency-domain optical coherence tomography in men and women with stable CAD. RESULTS: A total of 181 (139 were in men and 42 in women) plaques from 138 patients were analyzed. The mean age was similar between men and women. Besides an overall absence of significant differences in the vast majority of risk factors and comorbidities, men had a higher prevalence of active smoking (19 vs. 2%, P=0.006), previous myocardial infarction (17 vs. 2%, P=0.01), and previous percutaneous coronary interventions (42 vs. 17%, P=0.003). Frequency-domain optical coherence tomography in women showed significantly more plaque-vulnerability features as testified by higher percent of lipid-rich plaques (55 vs. 36%, P=0.03), macrophages (21 vs. 5%, P=0.003), and microvessels (24 vs. 8%, P=0.01). Multivariate analysis showed that female sex was associated independently with lipid-rich plaques (P=0.034) and macrophages (P=0.001). In the analysis restricted to the more severe lesions that were revascularized, women continued to be characterized by more adverse morphological features, such as macrophages (30 vs. 7%, P=0.004) and lipid-rich plaques (63 vs. 39%, P=0.045). CONCLUSION: Women with stable CAD may be characterized by plaques that have increased prevalence of vulnerability compared with men. These findings support the hypothesis of sex-specific differences in the development of atherosclerosis.

Continuum of Vasodilator Stress From Rest to Contrast Medium to Adenosine Hyperemia for Fractional Flow Reserve Assessment.

OBJECTIVES: This study compared the diagnostic performance with adenosine-derived fractional flow reserve (FFR) ≤0.8 of contrast-based FFR (cFFR), resting distal pressure (Pd)/aortic pressure (Pa), and the instantaneous wave-free ratio (iFR). BACKGROUND: FFR objectively identifies lesions that benefit from medical therapy versus revascularization. However, FFR requires maximal vasodilation, usually achieved with adenosine. Radiographic contrast injection causes submaximal coronary hyperemia. Therefore, intracoronary contrast could provide an easy and inexpensive tool for predicting FFR. METHODS: We recruited patients undergoing routine FFR assessment and made paired, repeated measurements of all physiology metrics (Pd/Pa, iFR, cFFR, and FFR). Contrast medium and dose were per local practice, as was the dose of intracoronary adenosine. Operators were encouraged to perform both intracoronary and intravenous adenosine assessments and a final drift check to assess wire calibration. A central core lab analyzed blinded pressure tracings in a standardized fashion. RESULTS: A total of 763 subjects were enrolled from 12 international centers. Contrast volume was 8 ± 2 ml per measurement, and 8 different contrast media were used. Repeated measurements of each metric showed a bias <0.005, but a lower SD (less variability) for cFFR than resting indexes. Although Pd/Pa and iFR demonstrated equivalent performance against FFR ≤0.8 (78.5% vs. 79.9% accuracy; p = 0.78; area under the receiver-operating characteristic curve: 0.875 vs. 0.881; p = 0.35), cFFR improved both metrics (85.8% accuracy and 0.930 area; p < 0.001 for each) with an optimal binary threshold of 0.83. A hybrid decision-making strategy using cFFR required adenosine less often than when based on either Pd/Pa or iFR. CONCLUSIONS: cFFR provides diagnostic performance superior to that of Pd/Pa or iFR for predicting FFR. For clinical scenarios or health care systems in which adenosine is contraindicated or prohibitively expensive, cFFR offers a universal technique to simplify invasive coronary physiological assessments. Yet FFR remains the reference standard for diagnostic certainty as even cFFR reached only ∼85% agreement.

Growth properties of cardiac stem cells are a novel biomarker of patients' outcome after coronary bypass surgery.

BACKGROUND: The efficacy of bypass surgery in patients with ischemic cardiomyopathy is not easily predictable; preoperative clinical conditions may be similar, but the outcome may differ significantly. We hypothesized that the growth reserve of cardiac stem cells (CSCs) and circulating cytokines promoting CSC activation are critical determinants of ventricular remodeling in this patient population. METHODS AND RESULTS: To document the growth kinetics of CSCs, population-doubling time, telomere length, telomerase activity, and insulin-like growth factor-1 receptor expression were measured in CSCs isolated from 38 patients undergoing bypass surgery. Additionally, the blood levels of insulin-like growth factor-1, hepatocyte growth factor, and vascular endothelial growth factor were evaluated. The variables of CSC growth were expressed as a function of the changes in wall thickness, chamber diameter and volume, ventricular mass-to-chamber volume ratio, and ejection fraction, before and 12 months after surgery. A high correlation was found between indices of CSC function and cardiac anatomy. Negative ventricular remodeling was not observed if CSCs retained a significant growth reserve. The high concentration of insulin-like growth factor-1 systemically pointed to the insulin-like growth factor-1-insulin-like growth factor-1 receptor system as a major player in the adaptive response of the myocardium. hepatocyte growth factor, a mediator of CSC migration, was also high in these patients preoperatively, as was vascular endothelial growth factor, possibly reflecting the vascular growth needed before bypass surgery. Conversely, a decline in CSC growth was coupled with wall thinning, chamber dilation, and depressed ejection fraction. CONCLUSIONS: The telomere-telomerase axis, population-doubling time, and insulin-like growth factor-1 receptor expression in CSCs, together with a high circulating level of insulin-like growth factor-1, represent a novel biomarker able to predict the evolution of ischemic cardiomyopathy following revascularization.

Characterization of microvascular and myocardial damage within perfusion defect area at myocardial contrast echocardiography in the subacute phase of myocardial infarction.

AIMS: The anatomical correlates of perfusion defect (PD) at myocardial contrast echocardiography (MCE) in the subacute phase of ST-elevation myocardial infarction (STEMI) are currently unknown. The study aimed at assessing whether, in the subacute phase of STEMI, within MCE PD microvessels are anatomically damaged or if some vasodilation can be still elicited and if the PD correlates with the extent of myocardial necrosis. METHODS AND RESULTS: Twenty-two post-percutaneous coronary intervention (PCI) patients underwent MCE 7 ± 1 days after STEMI, at baseline and after adenosine (ADN) administration. An area of completely non-opacified myocardium, corresponding to the area of the PD, was quantitated by planimetry. The area of the PD on MCE was compared with biochemical and imaging measures of myocardial necrosis: cardiac Troponin T peak (cTnT peak) and hyperenhanced area at gadolinium-enhanced cardiac magnetic resonance (Gd-CMR), respectively. After vasodilator stimulus, the area of the PD remained significantly unchanged when compared with the baseline value (P = 0.09 vs. baseline). The MCE index correlated at baseline with cTnT peak and Gd-CMR assessments of myocardial necrosis (P < 0.001). Also after ADN infusion, correlations between PD and extent of myocardial necrosis were similar to that assessed at baseline. CONCLUSION: When assessed in the subacute phase of STEMI, the extent of the PD on MCE represents an area of both myocardial and microvascular necrosis.

Differential levels of circulating progenitor cells in acute coronary syndrome patients with a first event versus patients with recurring events.

OBJECTIVE: Pathophysiology of acute coronary syndromes in patients presenting with a first cardiac event (FCE) can be different from patients with a recurring cardiac event (RCE). We assessed inflammatory activation and circulating progenitor cells' (CPC) mobilisation in patients with a FCE versus those with RCE. METHODS: We recruited 41 patients: 18 with FCE and 23 with RCE. Peripheral blood samples were drawn at baseline and at 20 days to measure high sensitivity C-reactive protein (CRP) and to assess CD34+/133+ CPC and CD34+/KDR+ CPC by flow cytometry. RESULTS: CD34+/133+ cells (% number of cells per total number of cytometric events) were similar at baseline, being 0.25% (0.17-0.42%) in the FCE vs 0.23% (0.11-0.43%) in the RCE group, and increased at follow-up only in the FCE group to 0.41% (0.22-0.64%), while in the RCE group they were 0.27% (0.11-0.36%) (p=0.009 for the interaction, p=0.07 for the main effect of time). CD34+/KDR+ cells were similar at baseline in the two groups, did not significantly increase over time (p=0.2), and no differential effect of FCE vs RCE over time was seen (p=0.38). CRP levels, similar at baseline, were consistently reduced at 20 days after ACS (p=0.001), with no differential effect of FCE vs RCE pts (p=0.74). Variation from baseline to follow-up for both CD34+/133+ and CD34+/KDR+ did not correlate with either baseline CRP or delta CRP. CONCLUSIONS: Our data demonstrate a differential CPC mobilization behavior for FCE patients compared to RCE ones, independent of inflammatory activation.

Cystatin C is associated with an increased coronary atherosclerotic burden and a stable plaque phenotype in patients with ischemic heart disease and normal glomerular filtration rate.

OBJECTIVE: Cystatin C (Cys-C) is an accurate marker of renal function. Recent studies have shown that serum Cys-C levels predict the risk of cardiovascular events. The causes of this association, however, are largely unknown. METHODS AND RESULTS: Seventy consecutive patients (age 62+/-12, male sex 87%) undergoing coronary angiography because of typical chest pain and found to have coronary artery disease were included in the present study. Patients with abnormal creatinine-derived glomerular filtration rate (<90ml/min/1.73m(2)) were excluded in order to avoid the well-known effect of overt renal insufficiency on coronary atherosclerosis. Coronary angiography was evaluated by two expert angiographers who assessed disease severity and extent according to the Sullivan's score and lesion morphology. In all patients, Cys-C and C-Reactive Protein (CRP) serum levels were measured on admission. Multivariable analysis was performed to assess independent predictors of angiographic measures. Diabetes was the only predictor of disease severity (p=0.005), while male sex (p=0.03), hypercholesterolemia (p=0.04), diabetes (p<0.0001) and Cys-C (p<0.0001) were independent predictors of disease extent. Independent predictors of smooth lesions were diabetes (p<0.001) and Cys-C (p=0.005). No correlation was found between Cys-C and CRP serum levels (p=0.6). CONCLUSION: Cys-C is associated with coronary atherosclerosis extent and a smooth lesion morphology. The long-term prognostic role of Cys-C might be accounted for by a greater atherosclerotic burden, a necessary substrate for plaque destabilization.