Abstract Background Mitral regurgitation (MR) is commonly observed following acute myocardial infarction (MI). Localised left ventricular (LV) remodelling in the region of papillary muscles together with impaired myocardial contractility promote MR. There is a paucity of long-term follow-up studies to determine whether the severity of MR observed post-MI, changes with time. Purpose This study retrospectively followed up patients with MR detected following acute MI (AMI) to investigate changes in MR severity with time and assess for pre-discharge predictors of MR regression or progression. Methods Clinical records of 1000 patients admitted with AMI between 2016 and 2017 to a single centre were retrospectively interrogated. One hundred and nine patients met the inclusion criteria of MR on pre-discharge transthoracic echocardiography (TTE) and follow-up TTE scans. Echocardiographic parameters were investigated to determine predictors of progression or regression at follow-up. Patients were divided according to those who had early follow-up TTE (within 1-year) and late follow-up TTE (beyond 1-year). Results Early follow-up TTE was performed in 73 patients at a median of 6 (IQR 3–9) months. Patients had a mean age of 69±13 years and were predominantly male 50/73 (68%). At baseline, relative MR severities were: 49/73 (67%) mild MR, 23/73 (32%) moderate MR and 1 (1%) severe MR. At follow-up, MR had completely resolved in 18/73 (23%) patients, while 39/73 (53%) had mild MR, 15/73 (21%) moderate MR and 1 (1%) severe MR. Compared to patients with no resolution of MR, those with completel resolution were younger (mean age 62±16 vs 72±11 years; p=0.015) but there were no other significant differences between the groups. Resolution at early follow-up did not significantly influence long-term mortality rates. Late follow-up TTE was performed in 69 patients at a median 2.4 (IQR 2–3.2) years. Pre-discharge, 49/69 (71%) patients had mild MR and 20/69 (29%) moderate MR. At follow-up, MR had completely resolved in 18/69 (26%), and amongst patients with persistent MR, proportion of severities were: 37/69 (54%) mild MR, 11/69 (16%) moderate MR and 3/69 (4%) severe MR. Patients with progression of mild MR were more likely to have lower left ventricular ejection fraction (LVEF: 47±15 vs 57±12%; p=0.010) and greater indexed left ventricular end-systolic volume (LVESVi: 37±23 vs 25±14 ml/m2; p<0.001) on pre-discharge TTE. Resolution of MR at late follow-up was associated with a reduction in long-term mortality [deaths: 2/55 (3%) vs 3/14 (21%); p=0.022] at a mean follow-up of 4.2 years from MI. Conclusion MR observed following AMI completely resolved in approximately one-quarter of patients at 6-month and 2-year follow-up. Progression of mild MR at long-term follow-up appears to be associated with increased mortality and is predicted by lower LVEF and greater LVESVi pre-discharge. Funding Acknowledgement Type of funding sources: None.

Background Antiplatelet agents reduce recurrence after cerebral ischaemia but are not effective in all patients, in part because of treatment resistance. The primary aim was to assess the proportion of patients who are insensitive to clopidogrel. The secondary aim was to assess the association between insensitivity to clopidogrel and recurrent cerebrovascular events. Methods Following written informed consent, independent patients with a recent non-cardioembolic ischaemic stroke or transient ischaemic attack, and taking clopidogrel, were enrolled. Platelet function was assessed with remote measurement of surface expression of P-selectin (CD62P) using commercial kits sensitive to aspirin or clopidogrel. Participants' general practitioners provided details on recurrent vascular events at least 90 days later. Data are mean (SD) and median [IQR]. Resistance was defined as: aspirin median fluorescence (MF) >500 units, clopidogrel MF >860 units. Non-parametric descriptors and tests were used. Results 63 patients were recruited: mean age 64 (13.7) years, women 47%. At baseline, 59 (95%) patients were taking clopidogrel alone with 3 (5%) on combined clopidogrel and aspirin. Assessment of platelet surface P-selectin revealed: aspirin test 528 [317, 834], >500 54.8%; clopidogrel test 429 [303, 656], >860 11.3%. No participants on aspirin and clopidogrel showed aspirin resistance. Thirteen (20.6%) patients had a recurrent cerebrovascular event; those with an ischaemic stroke had a non-significantly higher baseline P-selectin using the clopidogrel test as compared with those with no recurrence: 626 [380, 801] versus 406 [265, 609], p=0.08. Conclusions Remote measurement of platelet function assessed using the platelet surface expression of P-selectin is feasible. 11% of patients taking clopidogrel showed resistance. No significant associations were noted between clopidogrel resistance and recurrent ischaemic events.

Type of funding sources: None. Left ventricular systolic dysfunction (LVSD) is a common consequence of myocardial infarction (MI). Data from historic series identified LVSD in up to 60% of patients post-MI. However, in modern practice, with high-sensitivity cardiac biomarkers leading to early detection of MI and widespread use of early revascularization, the prevalence of LVSD in the acute phase of MI and its impact on subsequent clinical heart failure remains unknown. To ascertain the prevalence of LVSD on pre-discharge echocardiography and its impact on subsequent clinical heart failure after type 1 MI treated with percutaneous coronary intervention (PCI) in a UK tertiary cardiac centre. A retrospective electronic patient records review of consecutive patients with type 1 MI treated with PCI between January 2016 - December 2017. Patients treated conservatively or with surgical revascularization were excluded. 1000 consecutive patients were identified and 948/1000 who had an inpatient echocardiogram prior to discharge were included in this analysis – 413 ST elevation MI (STEMI) and 535 non-ST elevation (NSTEMI). Median door to balloon time for STEMI was 42 minutes (IQR 28-79). Median time from symptom onset to intervention for NSTEMI was 3 days (IQR 1-6). LVSD was defined as left ventricular ejection fraction (LVEF) <50% on transthoracic echocardiogram carried out during the hospital episode. LVSD was significantly more prevalent in patients with STEMI compared to NSTEMI (37.4% vs 17.3%, p < 0.001). Median LVEF was significantly lower in the STEMI population (55%, IQR 45-60) compared to patients with NSTEMI (60%, IQR 54-65), p < 0.001. However, rates of clinical heart failure at index presentation with MI did not vary significantly between STEMI and NSTEMI patients (6.1% vs 4.9%, p = 0.414). In stepwise multivariate regression models: age, peak troponin and previous coronary artery bypass grafting were predictors of LVEF, whereas LVEF and previous MI were predictors of clinical heart failure Patients with LVSD on pre-discharge echocardiography had significantly higher rates of 30-day readmission with heart failure (2.9% vs 0.7%, p = 0.017), 30-day all-cause mortality (6.1% vs 2%, p = 0.001), 30-day cardiac mortality (5.7% vs 1%, p < 0.001) and 2-year all-cause mortality (5.7% vs 1.6%, p = 0.001). However, at 2-years, there was no difference in hospital readmission with heart failure (0.8% vs 0.3%, p = 0.276). There were no significant differences between STEMI and NSTEMI patients for these endpoints. Early revascularisation with PCI has led to a reduction in the prevalence of early LVSD post-MI compared to historical data. However, the presence of LVSD remains a powerful predictor of adverse clinical outcomes. Despite lower rates of LVSD on pre-discharge echocardiography in patients with NSTEMI compared with STEMI, the incidence of subsequent clinical heart failure is similar. This however may be underestimated due to survival bias.

Previous studies of the incidence and severity of mitral regurgitation (MR) following acute myocardial infarction (MI) were limited by the study population (ST-elevation MI only), by diagnostic methods (lack of multiparametric quantification), or by the time-frame of study (late assessment post-MI). The true incidence of ischaemic MR (IMR) immediately following type 1 MI [non-ST-elevation (NSTEMI) and ST-elevation (STEMI)] patients in the modern era of universal early revascularisation remains unclear. Since even mild IMR confers a poor prognosis, factors which promote or protect against the development of MR require further evaluation. To determine the incidence, clinical and angiographic characteristics of patients with IMR following type 1 MI treated with PCI. This was a single-centre study of 1000 consecutive, prospectively recruited patients admitted to the Queen Elizabeth Hospital Birmingham with type 1 MI who underwent PCI. Early inpatient transthoracic echocardiography (TTE) was performed by accredited echocardiographers using standard multiparametric quantification. MR was observed in 294/1000 patients (29.4%) post-MI, graded as mild (76%), moderate (21%) and severe (3%). Median time from symptom onset to PCI was 1 day (IQR 0–4) and to TTE 2 days (IQR 1–3). Compared to patients without MR (MR-), those with MR (MR+) were older (73±12 years vs 66±13 years; p<0.001), male (75% vs 64%; p<0.001) and more likely to have a history of hypertension (HTN) (63% vs 55%; p=0.0117), heart failure (HF) (3.4% vs 1.1%; p=0.0140) and previous MI (28% vs 20%; p<0.005). MR+ patients more frequently presented with HF (8.5% vs 4.2%; p=0.0075), lower LV ejection fraction (LVEF) (50±14% vs 55±11%; p<0.001) and higher peak high sensitivity troponin T (765ng/L, IQR 170–3032 vs 400ng/L, IQR 51–1966; p<0.0001). MR+ patients were more likely to have severe disease in the left circumflex (LCx) (50% vs 33%; p<0.0001) or right coronary artery (RCA) (51% vs 43%; p=0.0135). Incidence of severe disease in the left main stem and left anterior descending artery (LAD) did not significantly differ between the two groups. Incidence of MR was equal (29%) amongst STEMI (126/431) and NSTEMI (168/569) patients. While the time to revascularisation did not affect the prevalence of MR following STEMI (linear regression analysis of door-to-balloon time in MR+ and MR- patients p=0.843), NSTEMI patients were more likely to develop MR if revascularisation was delayed (linear regression analysis of symptom onset to PCI time MR+ vs MR- p=0.061). Almost 1/3 of patients with type 1 MI undergoing revascularisation have MR evident on pre-discharge TTE. Factors promoting MR include older age, male sex, HTN, HF, larger non-LAD territory infarct, and depressed LVEF. The incidence of MR following STEMIs and NSTEMIs is equal. Earlier revascularisation is unlikely to reduce MR in STEMI patients but may improve MR prevalence following NSTEMI. Type of funding source: None

Abstract Background Ischaemic mitral regurgitation (IMR) confers a poor prognosis. Transcatheter intervention may improve survival but benefit is likely to depend on severity of IMR relative to LV remodelling following myocardial infarction (MI). In theory, those with “discordant” IMR (significant regurgitant volume without severe LV dilatation or impairment), are expected to benefit most from mitral intervention. While subcategorization may help to inform treatment, there are no data on post-MI patients in this respect. Purpose To determine the incidence of discordant & concordant IMR categorised on echocardiography post-MI and impact on outcomes. Methods 1000 consecutive patients admitted to our hospital with myocardial infarction who underwent coronary angioplasty were included. Early inpatient TTE was performed by accredited echocardiographers using standard multiparametric quantification. Using TTE parameters, 4 subgroups were identified (figure) according to the degree of MR relative to LV remodelling. Thresholds were based on European guidelines (± 2SD from normal) and median value among survivors for vena contracta (VC): – LVEF: 52% (♂), 54% (♀) – Indexed LV end diastolic volume (LVEDVi): 74ml/m2 (♂), 61ml/m2 (♀) – Effective regurgitant orifice area (EROA) ≥0.2cm2 – Regurgitant volume (RVol) ≥30ml – VC ≥0.5cm Results MR was seen in 294/1000 patients (29.4%) with a severity of mild (76%), moderate (21%) and severe (3%). Concordant and discordant IMR were each seen in 16/294 (5%) of IMR patients post-MI. After a mean follow up of 3.2 years, IMR patients had a 3% rate of heart failure (HF) within 1 year and 19% mortality. Non-survivors had significantly worse IMR (PISA 0.65±0.25cm vs 0.54±0.19cm; p=0.033; VC 0.63±0.25cm vs 0.49±0.18cm; p=0.014), worse LV function (LVEF 44±17% vs 51±13%; p<0.001), larger LV (LVEDVi 67±23ml/m2 vs 60±22ml/m2; p=0.032) and larger indexed LA volume (LAVi) (44±22ml vs 35±15ml; p<0.001). Those with concordant IMR had the worst survival (50%) although almost 1 in 5 of those with discordant MR died within the follow up period (19%). Using multivariable Cox regression, significant predictors of mortality included LVEF (p<0.001; HR 0.96, 0.94–0.98) and LAVi (p<0.001; HR 1.02, 1.01–1.03) but not LVEDVi. Conclusion 1) Significant predictors of mortality in IMR include LA dilatation and decline in LVEF, but not LV dilatation. 2) Although discordant severe IMR is uncommon following MI, mortality if left untreated remains high. Attention should be paid to early selection of this cohort for intervention. Funding Acknowledgement Type of funding source: None

Remote ischaemic per‐conditioning (RIC) is neuroprotective in experimental ischaemic stroke. Several neurohumoral, vascular and inflammatory mediators are implicated. The effect of RIC on plasma biomarkers was assessed using clinical data from the REmote ischaemic Conditioning After Stroke Trial (RECAST‐1).

Background and Purpose: In order to assess the association of microparticles derived from activated platelets (PMP) or endothelial cells (EMP) with risk markers for recurrent embolic events in patients with symptomatic carotid artery disease, we studied the associations between PMP/EMP and three risk markers: plaque haemorrhage (PH), micro-embolic signals and cerebral diffusion abnormalities. Methods: Patients with recently symptomatic high-grade carotid artery stenosis (60–99%, 42 patients, 31 men; mean age 75 ± 8 years) and 30 healthy volunteers (HV, 11 men; mean age 56 ± 12 years) were prospectively recruited. Patients were characterised by carotid magnetic resonance imaging (presence of PH [MRI PH]), brain diffusion MRI (cerebral ischaemia [DWI+]) and transcranial Doppler ultrasound (micro-embolic signals [MES+]). PMP and EMP were classified by flow cytometry and expressed as log-transformed counts per microlitre. Results: MES+ patients (n = 18) had elevated PMP (MES+ 9.61 ± 0.57) compared to HV (8.80 ± 0.73; p < 0.0001) and to MES– patients (8.55 ± 0.85; p < 0.0001). Stroke patients had elevated PMP (9.49 ± 0.64) and EMP (6.13 ± 1.0) compared to non-stroke patients (PMP 8.81 ± 0.73, p = 0.026, EMP 5.52 ± 0.65, p = 0.011) and HV (PMP 8.80 ± 0.73, p = 0.007, and EMP 5.44 ± 0.47, p = 0.006). DWI+ patients (n = 16) showed elevated PMP (DWI+ 9.53 ± 0.64; vs. HV, p = 0.002) and EMP (DWI+ 5.91 ± 0.99 vs. HV 5.44 ± 0.47; p = 0.037). Only PMP but not EMP were higher in DWI+ versus DWI– patients (8.67 ± 0.90; p = 0.002). No association was found between PMP and EMP with MRI PH. Conclusions: PMP and EMP were associated with stroke and recent cerebrovascular events (DWI+) but only PMP were also associated with ongoing (MES+) thrombo-embolic activity suggesting a differential biomarker potential for EMP to index cerebral ischaemia while PMP may predict on-going thrombo-embolic activity.

Background: Cilostazol and isosorbide mononitrate (ISMN) are candidate treatments for cerebral small vessel disease and lacunar ischaemic stroke. As both drugs may influence hemoglobin and platelet count, and hemodynamics, we sought to assess their effects in the lacunar intervention-1 (LACI-1) trial. Methods: Fifty-seven lacunar ischaemic stroke patients were randomized to immediate ISMN, cilostazol, or their combination for 9 weeks in addition to guideline stroke prevention. A fourth group received both drugs with a delayed start. Full blood count, platelet function, peripheral blood pressure (BP), heart rate and central hemodynamics (Augmentation index, Buckberg index) were measured at baseline, and weeks 3 and 8. Differences were assessed by multiple linear regression adjusted for baseline and key prognostic variables. Registration ISRCTN 12580546. Results: At week 8, platelet count was higher with cilostazol vs. no cilostazol (mean difference, MD 35.73, 95% confidence intervals, 95% CI 2.81-68.66, p = 0.033), but no significant differences were noted for hemoglobin levels or platelet function. At week 8, BP did not differ between the treatment groups, whilst heart rate was higher in those taking cilostazol vs. no cilostazol (MD 6.42, 95% CI 1.17-11.68, p = 0.017). Buckberg index (subendocardial perfusion) was lower in those randomized to cilostazol vs. no cilostazol and in those randomized to both drugs vs. either drug. Whilst ISMN significantly increased unadjusted augmentation index (arterial stiffness, MD 21.19, 95% CI 9.08-33.31, p = 0.001), in isolation both drugs non-significantly reduced augmentation index adjusted for heart rate. Conclusions: Cilostazol increased heart rate and platelet count, and reduced Buckberg index, whilst both drugs may individually reduce arterial stiffness adjusted for heart rate. Neither drug had clinically significant effects on hemoglobin or platelet function over 8 weeks. Further assessment of the safety and efficacy of these medications following lacunar ischaemic stroke is warranted.

Measurement of P-selectin on activated platelets as a means of measuring platelet function utilizing the technology described here has the advantage of not requiring immediate access to specialist equipment and expertise. Blood samples are activated, fixed, stored, and transported to a central laboratory for flow cytometric analysis. Here we have compared P-selectin with other more traditional approaches to measuring platelet function in blood and/or platelet-rich plasma (PRP) from patients with acute coronary syndromes on treatment for at least 1 month with either aspirin and clopidogrel or aspirin with prasugrel. The comparators were light transmission aggregometry (LTA), VerifyNow and Multiplate aggregometry (for determining the effects of aspirin) and LTA, VerifyNow and Multiplate together with the BioCytex VASP phosphorylation assay (for the P2Y(12) antagonists). The P-selectin Aspirin Test revealed substantial inhibition of platelet function in all but three of 96 patients receiving aspirin with clopidogrel and in none of 51 patients receiving aspirin and prasugrel. The results were very similar to those obtained using LTA. There was only one patient with high residual platelet aggregation and low P-selectin expression. The same patients identified as "non-responders" to aspirin also presented with the highest residual platelet activity as measured using the VerifyNow system, although not quite as well separated from the other values. With the Multiplate test only one of these patients clearly stood out from the others. The results obtained using the P-selectin P2Y(12) Test in 102 patients taking aspirin and clopidogrel were similar to the more traditional approaches in that a wide scatter of results was obtained. Generally, high values seen with the P-selectin P2Y(12) Test were also high with the LTA, VerifyNow, Multiplate, and BioCytex VASP P2Y(12) Tests. Similarly, low residual platelet function using the P2Y(12) test was seen irrespective of the testing procedure used. However, there were differences in some patients. Prasugrel was always more effective than clopidogrel in inhibiting platelet function with none of 56 patients (P-selectin and VerifyNow), only 2 of 56 patients (Multiplate) and only 3 of 56 patients (Biocytex VASP) demonstrating high on-treatment residual platelet reactivity (HRPR) defined using previously published cut-off values. The exception was LTA where there were 11 of 56 patients with HRPR. It remains to be seen which experimental approach provides the most useful information regarding outcomes after adjusting therapies in treated patients.

Vascular diseases such as myocardial infarction and ischemic stroke are associated with increased platelet function whilst the risk of recurrence is reduced by antiplatelet agents such as aspirin, clopidogrel, and prasugrel. However, some patients exhibit high platelet reactivity, especially with clopidogrel. Existing platelet function tests may not be ideal in that they can be expensive, are often time consuming, and measurements must be made near to the patient and within a few hours of blood collection. Platelet activation leads to translocation of P-selectin from alpha-granules to the cell surface. Following activation with arachidonic acid (which is blocked by aspirin) or adenosine diphosphate (inhibited by clopidogrel) and fixation, samples may be stored or posted to a laboratory performing flow cytometric quantification of platelet P-selectin expression. Acute myocardial infarction and ischemic stroke are associated with high platelet reactivity on clopidogrel in 6-58% of patients when assessed with P-selectin expression, and high reactivity was associated with an increased risk of recurrence after myocardial infarction. Use of P-selectin expression tests may also be of relevance to surgical and veterinary practice and the diagnosis of mild bleeding disorders. The present review explores this topic in further detail.

Background: Platelet activity may be measured remotely as surface P-selectin expression and varies between antiplatelet agents and patient responses to them. Methods: In TARDIS, patients with acute non-cardioembolic ischaemic stroke or transient ischaemic attack were randomised to intensive (combined aspirin, clopidogrel and dipyridamole, ACD) or guideline antiplatelets (combined aspirin and dipyridamole, AD; or clopidogrel alone, C). On-treatment platelet function, assessed as surface P-selectin expression, was measured remotely at 7 days post randomisation. The tests detected the effects of aspirin and of clopidogrel (Platelet Solutions Ltd). Data are mean difference (MD) with 95% confidence intervals (CI). Results: 626 patients (intensive 312, guideline AD 142, C 172) had P-selectin taken at day 7: mean age 68.3 (10.0), 66.3% male. In a comparison of on-treatment P-selectin (Table 1), the aspirin test showed that platelet reactivity was lower with ACD than AD (p=0.005) and C (p<0.001). ACD failed to suppress P-selectin levels below 500 units in 13 (4.4%) patients. Conversely, the clopidogrel test demonstrated that platelet reactivity was higher in patients receiving ACD than C (p=0.020). Treatment with C did not suppress P-selectin levels below 860 units in 22 (12.9%) patients. Conclusion: The aspirin test indicated that ACD was more effective in supressing stimulated platelet surface P-selectin than AD. However, the clopidogrel test showed treatment with C to be more effective than ACD, although 12.9% of patients had high residual platelet reactivity.

Background Antiplatelet medications are increasingly used in dogs. Remote analysis of platelet activity is challenging, limiting assessment of antiplatelet drug efficacy. Hypothesis/Objectives To evaluate a method used in humans for stimulation and remote analysis of canine platelet activity. Animals Forty‐five dogs of various ages without a coagulopathy or thrombocytopenia. Six were receiving antiplatelet medication. Methods Prospective observational study. Platelets were stimulated with combinations of arachidonic acid ( AA ) and epinephrine (Epi) or adenosine diphosphate ( ADP ) and the thromboxane A 2 ‐mimetic U46619 (U4). PAMF ix was added to the blood samples to facilitate delayed analysis of platelet activity. Activity was assessed by flow cytometric measurement of surface P‐selectin ( CD 62P) expression. Results Canine platelets could be stimulated with both AA /Epi and ADP /U4. The levels of P‐selectin were significantly greater than paired, unstimulated samples ( P < 0.001). Inhibition of P‐selectin expression occurred after this stimulation by adding antiplatelet drugs in vitro. The efficacy of antiplatelet drugs in samples from treated dogs was also measurable ex vivo using this method. Delayed analysis of platelet activity at time points up to 22 days demonstrated excellent correlation between respective mf values at each time point (r 2 = 0.92, P < 0.0001). Conclusions and Clinical Importance This study evaluated a new method to remotely assess canine platelet activity. It shows that PAMF ix can be used for this purpose. This provides opportunities to interrogate the inhibitory action of antiplatelet drugs in clinical settings.

Background. The TARDIS trial assessed the safety and efficacy of intensive versus guideline antiplatelet agents given for one month in patients with acute stroke or TIA. The aim of this substudy was to assess the effect of antiplatelet agents taken at baseline on platelet function reactivity and activation. Methods. Platelet function, assessed by remotely measured surface expression of P-selectin, was assessed in patients at their time of randomisation. Data are median fluorescence values. Results. The aspirin P-selectin test demonstrated that platelet expression was lower in 494 patients taking aspirin than in 162 patients not: mean 210 (SD 188) versus 570 (435), difference 360.3 (95% CI 312.2–408.4) (2p<0.001). Aspirin did not suppress P-selectin levels below 500 units in 23 (4.7%) patients. The clopidogrel test showed that platelet reactivity was lower in 97 patients taking clopidogrel than in 585 patients not: 655 (296) versus 969 (315), difference 314.5 (95% CI 247.3–381.7) (2p<0.001). Clopidogrel did not suppress P-selectin level below 860 units in 24 (24.7%) patients. Conclusions. Aspirin and clopidogrel suppress stimulated platelet P-selectin, although one-quarter of patients on clopidogrel have high on-treatment platelet reactivity. Platelet function testing may be performed remotely in the context of a large multicentre trial. Trial registration ISRCTN47823388.