Background: Increased hyperemic microcirculatory resistance and/or low coronary flow reserve (CFR) diagnostic criteria for coronary microvascular disease in ischemia with no obstructive coronary arteries (INOCA). For optimal therapy pathophysiological mechanisms need to be determined. Aim: To investigate plasma levels of markers of i) endothelial dysfunction (syndecan-1, E-selectin, thrombomodulin and hyaluronan) and ii) myocardial fibrosis (procollagen type I carboxy-terminal propeptide [PICP], suppression of tumorigenicity 2 [ST2], and tissue inhibitor of metalloproteinases-1[TIMP-1]) in relation to the index of microcirculatory resistance (IMR) and CFR in INOCA. Methods: Measurements of corrected IMR and CFR were determined in the LAD using thermodilution technique during coronary angiography (CA) in chronic coronary syndrome (CCS) patients. Plasma biomarkers were quantified using an ELISA and the association between each biomarker and i) IMR and ii) CFR was analyzed using linear regression. Results: We selected 162 random patients with INOCA from a cohort of 503 all-comer CCS patients with no congestive heart failure that underwent CA with measurements of CFR and IMR in the LAD. The mean age was 65 ±10 years and 101 (62.3%) were male. Median IMR and CFR were 19.1 (interquartile range [IQR] 11.9-30.7) and 3.5 (IQR 2.3-5.1) respectively. IMR was associated with syndecan-1 (Figure 1A) but not with PICP (Figure 1C) or the other biomarkers. CFR was inversely associated with syndecan-1 (Figure 1B), PICP (Figure 1D), and E-selectin (p=0.049). Conclusion: IMR is associated with increasing plasma levels of syndecan-1 but not with myocardial fibrosis, indicating endothelial dysfunction, with glycocalyx shedding, to be involved in high hyperemic microcirculatory resistance in INOCA. Low CFR is also associated with PICP indicating involvement of myocardial fibrosis in coronary microvascular disease in INOCA.

Background: The prognostic implications of coronary microvascular dysfunction in an all-comer cohort with chronic coronary syndrome (CCS) are not known. Aim: To investigate the association of baseline resistance index (BRI), index of microcirculatory resistance (IMR), and thermodilution-derived resting- and hyperemic flow velocities (RFV and HFV) with the primary composite endpoint consisting of all-cause mortality, incident myocardial infarction (MI) or hospitalization due to congestive heart failure (CHF) in CCS. Methods: CCS patients undergoing elective coronary angiography (CA) were included. Measurements of corrected IMR, BRI and mean transit time at baseline (Tmn base ) and during hyperemia (Tmn hyp ) were obtained in the LAD. RFV and HFV were calculated as 1/Tmn base and 1/Tmn hyp , respectively. Cox-regression was performed and Kaplan-Meier plots were constructed. Results: We included 503 patients before the coronary anatomy was known and thermodilution measurements in the LAD were obtained in 413 patients. Median age was 68 (IQR 61-74), 127 (25%) were women and 151 (37%) had a flow-limiting epicardial lesion in the LAD. Median follow-up was 5.3 years (IQR 3.0-6.6) and there were 57 events. Log 10 BRI was inversely associated with the primary endpoint before and after fractional flow reserve (FFR) adjustments (HR 0.64 [95% CI 0.42 - 0.97]; Figure 1A). Log 10 IMR was not associated with the primary endpoint (HR 0.94 [95% CI 0.61 - 1.5]; Figure 1B). Log 10 RFV was associated with the primary endpoint before and after FFR- adjustment (HR 1.8 [95% CI 1.2 - 2.7]) whereas log 10 HFV was not (HR 1.2 [95% CI 0.75-1.8]). Conclusion: Low microcirculatory resting resistance and high coronary resting flow velocity in the LAD, indicating impaired autoregulation, were associated with all-cause death, MI and/or CHF in CCS whereas hyperemic microcirculatory resistance and flow were not. Resting flow indices can be used for risk evaluation in patients with CCS undergoing CA. .

Background: Coronary microvascular dysfunction (CMVD) is associated with adverse cardiovascular outcome. We aimed to determine the prevalence of CMVD and factors related to index of microcirculatory resistance (IMR) in consecutive patients with chronic coronary syndrome (CCS) undergoing elective coronary angiography. Methods and results: Non-interventional physicians enrolled 274 patients with CCS before angiography, to minimize selection bias by PCI-operators. Fractional flow reserve (FFR) and IMR were measured in the LAD. Subjects with extensively diseased LAD, no measures due to technical reasons or violation of protocol were excluded from the analysis (n = 54). The proportion of patients with IMR corrected for collateral flow (IMRcorr) 25 units was 25% (95% confidence interval [CI] 19%-31%) in all 220 patients. In subjects with FFR <= 0.80 in the LAD the proportion of IMRcorr > 25 units was 21% (95% CI 13%-30%) as compared to subjects with FFR >0.80, 29% (95% CI 21%- 36%), p = .268. Haemoglobin (p <.005; r2 = 0.084), FFR in the LAD (p = .001; r2 = 0.049), creatinine clearance (p = .001; r(2) = 0.049; inversely), and NT-proBNP (p = .038; r(2) = 0.021) were independently associated with IMRcorr in multivariate linear regression analysis. Conclusions: We report that IMRcorr is associated with renal dysfunction, NT-proBNP, FFR in the LAD and, for the first time, blood haemoglobin. One in four of patients referred for coronary angiography due to CCS have CMVD defined as IMRcorr > 25 in the LAD. (c) 2020 Elsevier B.V. All rights reserved.

Microvesicles (MVs) released from leukocytes, platelets and endothelial cells are elevated in patients with acute coronary syndrome (ACS). In the present study, we assessed the potential pro-aggregatory properties of MVs obtained from ACS patients. Thus, we divided the patients into two groups based on clopidogrel-responsiveness, i.e. high on-treatment platelet reactivity (HPR; n = 16), and low or normal on-treatment platelet reactivity (non-HPR; n = 14), respectively. MVs from patients were obtained by high-speed centrifugation, and the pro-aggregatory effect of MVs added to fresh isolated platelets from healthy subjects were analyzed by 96-well microplate aggregometry. MVs from HPR patients significantly enhanced spontaneous platelet aggregation around two times more than MVs from non-HPR patients. The pro-aggregatory effect of three out of four MV phenotypes correlated to MV-concentrations as determined by flow cytometry. Furthermore, MVs from patients with diabetes mellitus (n = 9) had a stronger pro-aggregatory effect compared to MVs from those without diabetes (n = 21; p = .025 between groups). In conclusion, MVs from ACS patients with clopidogrel non-responsiveness enhance platelet aggregation, as do MVs from ACS patients with diabetes. Thus, MVs from patients with hyperreactive platelets boost platelet aggregation. Blocking MV-formation may reduce platelet hyperreactivity.

Aim. To investigate the relationship between stent length and changes in microvascular resistance during PCI in stable coronary artery disease (CAD). Methods and Results. We measured fractional flow reserve (FFR), index of microcirculatory resistance (IMR), and coronary flow reserve (CFR) before and after stenting in 42 consecutive subjects with stable coronary artery undergoing PCI with stent in the LAD. Patients that had very long stent length (38–78 mm) had lower FFR before stenting than patients that had long (23–37 mm) and moderate (12–22 mm) stent length (0.59 (±0.16), 0.70 (±0.12), and 0.75 (±0.07); p=0.002). FFR improved after stenting and more so in subjects with very long stent length compared to long and moderate stent length (0.27 (s.d ± 16), 0.15 (s.d ± 0.12), and 0.12 (s.d ± 0.07); p for interaction = 0.013). Corrected IMR (IMRcorr) increased after stenting in subjects who had very long stent length, whereas IMRcorr was lower after stenting in subjects who had long or moderate stent length (4.6 (s.d. ± 10.7), −1.4 (s.d. ± 9,9), and −4.2 (s.d. ± 7.8); p for interaction = 0.009). Conclusions. Changes in IMR during PCI in the LAD in stable CAD seem to be related to total length of stents implanted, possibly influencing post-PCI FFR. Larger studies are needed to confirm the relationship.

Abstract Objectives. To investigate clinical outcome in unselected real-life patients with unprotected left main coronary artery (ULMCA) stenosis and determine factors associated with selection of revascularization strategy. Design. Consecutive patients with ULMCA stenosis at our institution in 2009–2013 (n = 308) were retrospectively analyzed with propensity score adjusted Cox proportional hazards models for outcome. Baseline characteristics in relation to selection of revascularization strategy were analyzed with multivariate logistic regression. Results. Patients that underwent PCI (n = 94) had a higher risk of major adverse cardiac and cerebrovascular events (MACCE; adjusted HR 2.13 [95% CI 1.08–4.19]) than patients that had CABG surgery but there was no difference in the combination of death and MI (adjusted HR 1.17 [95% CI 0.50–2.75]). Later year of index angiography, age, Euroscore II and angiographer favoring PCI was associated with PCI as revascularization strategy. Higher SYNTAX score, higher systolic blood pressure and angiographer favoring CABG was associated with CABG. Conclusions. In consecutive patients with ULMCA stenosis PCI is associated with higher MACCE rates than CABG but there is no difference in death and MI. Later year of index angiography, higher age, lower systolic blood pressure, higher predicted per-procedural surgical risk, less complex coronary anatomy and angiographer favoring PCI increased the probability of revascularization with PCI instead of CABG.

OBJECTIVES Decreased right ventricular (RV) longitudinal function following coronary artery bypass grafting (CABG), as assessed by tricuspid annular systolic excursion (TAPSE) and RV peak systolic velocity (RVS') is a known condition. We aimed to explore the feasibility of the right ventricular index of myocardial performance (RIMP) in the assessment of RV function after CABG at rest and during peak dobutamine stress echocardiography (DSE). METHODS Forty-two patients indicated for CABG were included in this study. Coronary angiography, DSE and exercise bicycle test were performed within 6 weeks before and 3 months after CABG. The RIMP, RVS' and TAPSE at the lateral tricuspid annulus were also assessed. The results were presented as mean ± standard deviation. RESULTS The RIMP improved after CABG both at rest (0.45 ± 0.11 before vs 0.38 ± 0.08 after CABG, P = 0.013) and during DSE (0.75 ± 0.23 vs 0.49 ± 0.14, P < 0.001). TAPSE declined significantly when comparing the values from before CABG to after CABG both at rest (23.9 ± 4.46 vs 14.6 ± 3.67, P < 0.001) and during DSE (20.9 ± 4.16 vs 11.9 ± 3.60, P < 0.001). RVS' also decreased after CABG both at rest (11.9 ± 2.40 vs 8.5 ± 1.93, P < 0.001) and during DSE (15.6 ± 4.30 vs 10.5 ± 3.21, P < 0.001). On the other hand, exercise capacity improved after CABG compared with baseline (128.4 ± 40.12 W vs 142.1 ± 46.73 W, P = 0.014). CONCLUSIONS RIMP improved after CABG both at rest and during DSE. The reduction in TAPSE and RVS' after CABG indicate reduced regional mechanical RV function along the long axis rather than reduced global RV function.

Background: Myocardial performance index (MPI) is an echocardiographic parameter that reflects left ventricular (LV) function. MPI determined by means of tissue Doppler imaging (TDI) at different LV sites (global MPI) and its long-term prognostic implications in congestive heart failure (HF) have not been evaluated.Methods and Results: A total of 110 patients with HF during acute hospitalization were followed for a mean of 5.0 years for survivors. The myocardial velocities at 4 different LV sites near the mitral annulus from apical views were recorded with the use of pulsed-wave TDI. From myocardial velocity profiles, the MPI at each LV site was calculated: MPI = (isovolumetric contraction time + isovolumetric relaxation time)/ejection time. The global MPI was calculated as the mean from the 4 LV sites. Mean ejection fraction was 25%. A total of 61 patients died during the study period. On multivariate analysis, only MPI emerged as an independent predictor of mortality. With a cutoff value of 0.67, the hazard ratio for cardiovascular mortality during the follow-up period was 13 (95% confidence interval 5.03-34.44; P <.001). A cutoff MPI value of >= 0.67 identified patient mortality during the study period with a sensitivity of 86% and a specificity of 79%.Conclusion: Global TDI-derived MPI in patients with HF is a powerful predictor of cardiovascular mortality in patients with systolic HF.

High on-treatment platelet reactivity (HPR) to clopidogrel has been shown to increase the risk of cardiovascular events. Platelet-derived microvesicles (PMVs) may be prothrombotic and contribute to the risk of recurrent events observed in patients with HPR. However, PMVs may also serve as biomarkers and be used to assess platelet function. We investigated the association between platelet responses to clopidogrel (measured by whole blood impedance aggregometry) and circulating PMVs in patients with acute coronary syndrome (ACS). Blood samples were obtained at discharge from 200 patients with ACS who had undergone percutaneous coronary intervention (PCI). All patients were loaded with aspirin and clopidogrel before PCI. ADP-induced whole blood impedance aggregometry and measurement of PMVs were performed. Cut-off values for HPR and other reactivity (i.e. normal on-treatment reactivity, NPR and low on-treatment reactivity, LPR) to clopidogrel were set according to data from large prospective studies. We measured PMVs as phosphatidylserine and CD42a positive vesicles, together with CD62P or CD40L, using flow cytometry. ADP-induced platelet aggregation revealed that approximately 20% of patients had HPR. Levels of PMVs were almost two-fold higher in the HPR group compared with patients without HPR (for both CD42a- and CD62P-positive PMVs, p < 0.01). Furthermore, patients with LPR to clopidogrel had significantly fewer PMVs exposing CD62P than patients with HPR or those with NPR to clopidogrel. Patients with HPR during clopidogrel treatment have elevated levels of circulating PMVs, indicating ongoing platelet activation despite clopidogrel treatment. Moreover, in patients with LPR to clopidogrel, circulating PMV numbers are decreased. Taken together, our data suggest that PMVs are potential biomarkers of antiplatelet responses to clopidogrel. If PMVs also have prognostic value after, ACS should be tested in future studies.

n engl j med 373;13 nejm.org september 24, 2015 1271 occurred at 137 centers throughout the world in the phase 3 trial, which suggests that the skills necessary to safely administer the combination therapy are widely available. Furthermore, and to Valsecchi’s point, among the 120 patients who discontinued combination therapy because of toxic effects, the response rate was 67.5%. To us, this supports the current guidelines for management of toxic effects and discontinuation of treatment, since it shows that high response rates can be observed in the context of no treatment-related deaths. Longer followup will be needed to assess the effect of treatment discontinuation on overall survival. James Larkin, M.D., Ph.D.

Aims Myocardial performance index ( MPI ) is a measure of combined systolic and diastolic myocardial function. In patients with coronary artery disease ( CAD ) an increase in MPI is consistent with myocardial dysfunction. The objectives of this study were to characterize the changes in MPI after coronary artery bypass graft ( CABG ) at rest and at peak dobutamine stress echocardiography ( DSE ). Methods and Results Thirty‐six patients diagnosed with CAD and accepted for CABG were studied by standard echocardiography and DSE 1 month prior and 3 month after CABG . The MPI was calculated using pulsed‐wave tissue Doppler imaging ( PW ‐ TDI ) of the left ventricular ( LV ) wall‐motion velocity. At baseline, ejection fraction ( EF ; 42.7 ± 8%) and wall‐motion score index ( WMSI ; 1.1 ± 0.2) were impaired at rest as well as at peak DSE ( EF ; 49.2 ± 9 and WMSI 1.4 ± 0.2). MPI was prolonged both at rest (0.61 ± 0.13) and at peak DSE (0.78 ± 0.16). After CABG , EF and WMSI did not improve at rest (43.7 ± 8% and 1.1 ± 0.2, respectively). On the other hand, MPI improved substantially both at rest (0.45 ± 0.08; P < 0.001) and at peak DSE (0.56 ± 0.1; P < 0.001). At peak DSE an improvement of EF (54.2 ± 9; P < 0.05) and WMSI (1.1 ± 0.16; P < 0.001) was seen as well. Conclusion Myocardial performance index shows significant improvement after CABG in patients with CAD both at rest and peak DSE and appears to be a sensitive measure of myocardial function.

OBJECTIVES:To investigate the value of tissue Doppler imaging (TDI) measurements of right ventricular (RV) systolic and diastolic function as a predictor of long term cardiovascular outcomes in patients with left ventricular (LV) systolic heart failure.BACKGROUND:In patients with LV systolic heart failure, RV function has been shown to be an important predictor of outcome. TDI is probably a clinically useful method for assessing RV function. The studies published so far have had a rather short follow-up period and have excluded patients with atrial fibrillation.METHODS:156 patients admitted to the cardiology department due to decompensated heart failure were included in this observational cohort study. 19% had atrial fibrillation. An echocardiographic examination was performed at entry to the study. The patients were then followed for a mean of 829 days. The primary endpoint was cardiovascular mortality or hospitalisation for decompensated heart failure.RESULTS:43 patients (28%) died from cardiovascular causes and 55 patients (35%) patients were hospitalised. 80 patients (51%) reached the study endpoint. Only age and a combined systolic and diastolic TDI parameter (s'r + e'r < 18.5 cm/s) of the right ventricle were independent predictors of cardiovascular outcome (HR 1.99, p=0.007).CONCLUSION:A combined measure of RV systolic and diastolic function, using TDI, can be used as an independent predictor of outcome in patients with LV systolic heart failure.

Platelet monitoring is presently under evaluation in the clinic as a tool to improve antiplatelet treatment in patients with coronary artery disease (CAD). Measuring platelet function has, however, many inherent problems. It is important not only to evaluate the method used, but also to evaluate and standardize sampling and sample handling. As platelet monitoring is often performed in connection to coronary angiography and percutaneous coronary interventions, arterial sampling may be more convenient. However, in the outpatient follow-up setting venous sampling is, for obvious reasons, more practical and convenient. In the present study we compared platelet aggregation in blood collected from the arterial sheath to blood collected from the antecubital vein using multiple electrode aggregometry in whole blood in 28 patients with CAD. We found that sampling from artery and vein give similar data and that an identical number of patients with insufficient antiplatelet responses ('low responders' to aspirin and clopidogrel, respectively, according to predefined criteria) were detected with respect to adenosine diphosphate induced and arachidonic-acid induced aggregation. Thus both arterial and venous blood samples can be used in the monitoring of platelet function when multiple electrode aggregometry is applied to detect 'low responders'.

Background: Right ventricular (RV) involvement in patients with ST elevation myocardial infarction (STEMI) is a clinically important problem. The aim of this study was to evaluate the use of tricuspid annular velocity assessed by Doppler tissue imaging (DTI) as a marker of RV involvement in patients with a first STEMI. Methods: Seventy‐one patients with a first STEMI were examined by echocardiography before discharge and after 6 months. The patients were compared to 31 healthy subjects (HS). The diagnosis of RV infarction was based on the presence of ≥ 1 mm ST elevation in the right precordial ECG lead V4R. Tricuspid annular systolic and diastolic velocities using pulsed‐wave DTI were recorded at the RV free wall. Results: At day 1, tricuspid annular velocities were significantly reduced in patients with, compared to those without, ST elevation in V4R (11.1 vs. 13.7 cm/sec, 9.4 vs. 13.1 cm/sec and 14.1 vs. 15.9 cm/sec for systolic, early, and late diastolic velocities, respectively; P < 0.01). With a cutoff value for a tricuspid annular systolic velocity of 13 cm/sec, sensitivity and specificity for identifying patients with ST elevation in V4R were 89% and 71%, respectively. After 6 months, both tricuspid annular systolic and diastolic velocities in patients with RV infarction had increased significantly, but only tricuspid annular systolic velocity was still reduced compared to HS (12.3 vs. 14.7 cm/sec; P < 0.01). Conclusion: Tricuspid annular velocities assessed by DTI may be used as a marker of RV involvement in the acute and the late phase after a first STEMI. (ECHOCARDIOGRAPHY 2010;27:139‐145)

Background: Inflammation is a major contributor to atherosclerotic vascular disease. Inflammatory parameters such as C-reactive protein (CRP) and Interleukin-6 (IL-6) have been shown to be strong predictors of cardiovascular events. The association between preoperative inflammatory parameters and early graft occlusion as well as cardiovascular events after coronary artery bypass grafting (CABG) has not, however, been fully elucidated. The aims of the present study were to prospectively investigate the prognostic value of the inflammatory parameters IL-6, CRP, and endothelin (ET-1) to predict early graft occlusion as well as late cardiovascular events after CABG.Methods: In the present study 99 patients undergoing CABG because of stable angina pectoris due to significant coronary artery disease were prospectively included. Coronary angiography was repeated 3 months after CABG in 81 patients in order to evaluate early graft occlusion. Blood samples were collected before CABG in all patients. Patients were followed up for a median of 5 (3-7) years after CABG.Results: Twenty-five patients (31%) had one or more occluded grafts at the 3-month control coronary angiography. The patients with occluded grafts had higher preoperative CRP and IL-6 levels in plasma [CRP 2.22 (1.11-4.47) mg/L vs. 1.23 (0.71-2.27) mg/L P= 0.03] and [IL-6 2.88 (1.91-5.94) pg/mL vs. 2.15 (1.54-3.14) pg/mL P= 0.006]. There were 23 late cardiovascular events among the 99 patients during the follow-up. Patients experiencing late cardiovascular events had higher preoperative IL-6 levels than those without late cardiovascular events [4.13 (1.83-5.87) pg/mL vs. 2.08 (1.53-2.29) pg/mL, P= 0.002] whereas CRP levels did not differ significantly between the two groups [1.5 (0.79-4.41) mg/L vs. 1.33 (0.74-2.48) mg/L, P= 0.41]. Looking at IL-6, a cut off value more than 3.8 pg/ml was associated with a significant higher risk for an early graft occlusion (P= 0.04) and late cardiovascular events (P= 0.00003). Preoperative endothelin-1 did not predict early graft occlusions or late cardiovascular events.Conclusions: Raised preoperative IL-6 levels are predictors of both early graft occlusion and late cardiovascular events after CABG. Elevated preoperative CRP levels can predict early graft occlusion after CABG. Endothelin did not differ between the two groups. (C) 2006 Elsevier Ireland Ltd. All rights reserved.

SummaryAims The aim of this study was to assess left ventricular (LV) systolic and diastolic function, using Doppler tissue imaging (DTI), in patients with complete recovery of visual wall motion abnormalities six months after a first ST‐elevation myocardial infarction (STEMI).Methods Out of 90 patients presenting with a STEMI, 68 patients without a history of heart disease were examined by echocardiography before discharge and after 6 months. The patients were compared to 41 age matched healthy subjects (HS). LV function was assessed by visual wall motion and mitral annular velocities using pulsed wave DTI.Results Sixty‐eight patients had visual wall motion abnormalities at baseline. Of these, 19 patients showed complete recovery of wall motion at 6‐months follow‐up. Patients with complete recovery of wall motion abnormalities had significantly reduced peak systolic and peak early diastolic mitral annular velocities compared to HS at 6 months (8·3 cm s−1 versus 9·9 cm s−1, P<0·001 for systolic velocity and 9·3 cm s−1 versus 13·1 cm s−1, P<0·001 for diastolic velocity, respectively).Conclusion In patients presenting with a first STEMI, mitral annular systolic and early diastolic velocities assessed by DTI at 6‐months follow‐up are significantly reduced compared to HS, despite normal standard echocardiographic parameters of LV function. This probably reflects a residual subendocardial damage not detected by conventional echocardiographic methods.