Timing of pulmonary valve replacement: can we use the same volumetric thresholds in repaired tetralogy of Fallot and pulmonary stenosis?

The timing of pulmonary valve replacement in patients with pulmonary regurgitation following treatment of pulmonary stenosis is undefined. Although cardiac magnetic resonance-based right ventricular volumes in tetralogy of Fallot patients have been used as a guide in pulmonary stenosis patients, anatomic differences between tetralogy of Fallot and pulmonary stenosis patients complicate their application to pulmonary stenosis patients and could result in late referral for pulmonary valve replacement. We sought to determine if pulmonary stenosis patients referred for pulmonary valve replacement were at greater risk for morbidity or need for tricuspid valve intervention at the time of pulmonary valve replacement. A retrospective cohort study was performed on all adult patients with a diagnosis of pulmonary stenosis or tetralogy of Fallot followed at our centre. Clinical and imaging-based exposures were collected. Pre-specified endpoints included need for concomitant tricuspid valve repair or replacement and pre- and post-pulmonary valve replacement cardiac magnetic resonance-based volumetric measurements. Between 1/1999 and 1/2020, 235 patients underwent pulmonary valve replacement for pulmonary regurgitation (52 with pulmonary stenosis, 183 with tetralogy of Fallot). Pulmonary stenosis patients were more likely to have at least moderate tricuspid regurgitation (p = 0.010), undergo concomitant tricuspid valve intervention (p = 0.003), and require tricuspid valve repair or replacement secondary to annular dilation (p = 0.027) compared to tetralogy of Fallot patients. There was no difference in pre-pulmonary valve replacement right ventricular size between pulmonary stenosis and tetralogy of Fallot patients. These findings suggest that referral for pulmonary valve replacement may be occurring later in the disease course for pulmonary stenosis patients.

Platelet reactivity in patients undergoing transcatheter aortic valve implantation.

Thromboembolic events, primarily stroke, might complicate transcatheter aortic-valve implantation (TAVI) procedures in 3-5 % of cases. Thus, it is common to administer aspirin and clopidogrel pharmacotherapy for 3-6 months following TAVI in order to prevent those events. The biologic response to the dual anti platelet treatment (DAPT) is heterogeneous, e.g. low response, known as high on treatment platelet reactivity (HTPR) may be associated with adverse thromboembolic events. Little is known about the prevalence of HTPR among patients undergoing TAVI. To assess the variability in response and rates of residual platelet reactivity in patients undergoing TAVI. We examined platelet reactivity in response to clopidogrel and aspirin in 40 consecutive patients (mean age 81.7 ± 6.5 years, 66.7 % women) who underwent successful TAVI using the VerifyNow P2Y12 assay and the multiple electrode aggregometry assay (Multiplate analyzer) in response to adenosine diphosphate and arachidonic acid respectively, at different time points before and following TAVI. Before TAVI, the majority of patients were on antiplatelet therapy (68.5 % aspirin, 12.5 % clopidogrel, 12.5 % DAPT). Following the procedure all patients were on DAPT or clopidogrel and warfarin. Among analyzed patients, 41 % had HTPR for clopidogrel and 12.5 % for aspirin at baseline, which did not significantly change 1-month following the procedure (p = 0.81 and p  = 0.33, respectively). In conclusion, patients undergoing TAVI for severe aortic stenosis and treated with DAPT have high rates of residual platelet reactivity during the peri-procedural period and up to 1-month thereafter. These findings may have clinical implications for the anti-platelet management of TAVI patients.

Comparison of platelet inhibition by prasugrel versus ticagrelor over time in patients with acute myocardial infarction.

High on-treatment platelet reactivity (HTPR) despite use of P2Y12 antagonists is associated with adverse cardiac events. The long-term variability in response to prasugrel and ticagrelor is unclear. Our aim was to assess residual platelet reactivity (PR) and rates of HTPR during treatment with prasugrel versus ticagrelor in patients with myocardial infarction (MI). 114 patients with MI treated with percutaneous coronary intervention (PCI) were included. Sixty-two patients were treated with prasugrel (mean age 58 ± 8 years, 21 % women, 29 % diabetes), and 52 patients with ticagrelor (mean age 63 ± 9, 19 % women, 37 % diabetes). Patients were tested for PR at 2-4 days and 30 days post-PCI, using the VerifyNow P2Y12 assay and the multiple-electrode aggregometry. Our results show a higher residual PR in patients treated with prasugrel than those treated with ticagrelor (VerifyNow: 65.4 ± 60.6 vs. 26.0 ± 24.2 P2Y12 reaction units, p < 0.001 at 2-4 days, and 67.3 ± 62.5 vs. 21.1 ± 26.1, p < 0.001 at follow-up). HTPR rates were higher in the prasugrel group (8.1-11.3 % vs. none with ticagrelor in the early test, and 8.7-10.9 % vs. none with ticagrelor at follow-up). In conclusion, in patients with MI undergoing PCI, treatment with ticagrelor resulted in greater platelet inhibition and lower HTPR rates compared with prasugrel, up to 30 days after the event.

Circulating reticulated platelets over time in patients with myocardial infarction treated with prasugrel or ticagrelor.

Reticulated platelets (RP) are young, hyperactive platelets that are increased during situations of enhanced platelet turnover such as acute myocardial infarction (AMI). The dynamics of RP levels after AMI is not established. We aimed to characterize the levels of circulating RP over time in patients with AMI. Patients with AMI treated with ticagrelor or prasugrel who underwent percutaneous coronary intervention (PCI) were tested for circulating RP using flow cytometry with Thiazole orange staining at 3 time points at 2-4 days, 30-60 days and 1 year post PCI. Platelet reactivity was assessed using the VerifyNow P2Y12 assay at these time points (results in platelet reactivity units-PRU). Thirty-five patients were included in the study (mean age 62.6 ± 9.1 years, 82.9 % males). Median RP levels were similar at the first and second time points (17.5 %, IQR 25-75: 10.8-22.4 % and 14.9 %, IQR 25-75: 9.7-26.8 %, respectively; p = 0.75). However, RP levels after 1 year were significantly lower as compared to the first and second time points (10.5 % (IQR 25-75: 5.3-18.1 %), p = 0.005 and p = 0.01, respectively). Residual platelet reactivity was very low at all 3 time points (median PRU 25, IQR 25-75: 7-53) and did not change significantly between them (p = 0.66). No significant correlation was found between levels of RP and PRU at any given time point. RP levels of patients with AMI treated with prasugrel or ticagrelor decrease over time after the acute event. However, RP levels over time do not correlate well with residual platelet reactivity.

Relation between ticagrelor response and levels of circulating reticulated platelets in patients with non-ST elevation acute coronary syndromes.

Antiplatelet responses to clopidogrel and prasugrel are highly variable and subject to significant rates of high on-treatment platelet reactivity (HTPR) after percutaneous coronary intervention (PCI). The proportion of circulating young reticulated platelets (RPs) inversely correlates with responsiveness to both agents. We aimed to determine the relationship between RPs and on-treatment platelet reactivity in ticagrelor-treated patients. Patients with non-ST-elevation acute coronary syndromes (NSTE-ACS) treated with PCI and ticagrelor were tested for platelet reactivity using the VerifyNow P2Y12 assay and multiplate aggregometry. RPs levels were determined using flow cytometry with thiazole orange staining. Tests were performed at 2-4 and 30 days post-PCI. Fifty three patients were included (mean age 62.6 ± 9.8 years, 18.9 % women, 35.8 % diabetes), of which 41 patients (77 %) completed follow-up. Variability in response to ticagrelor was very low according to both assays with no identified cases of HTPR at either time-point. In addition, there were no differences in platelet reactivity, as analyzed by the VerifyNow P2Y12 assay, or in the proportion of RPs between the two time points (p > 0.5). With the multiplate assay, platelet reactivity increased between the two time-points (8.6 ± 6.0 vs. 15.5 ± 11 AU*min; p = 0.0007). There was no significant correlation between RPs and platelet reactivity at both time-points and using both assays (p > 0.5). There were no cases of HTPR up to 30-days post-PCI in patients with NSTE-ACS treated with ticagrelor. In this cohort, no correlation between % RPs and platelet reactivity was observed. Attenuation of RP-induced platelet reactivity as a novel mechanism for ticagrelor's benefit requires further investigation.

The effect of dabigatran and rivaroxaban on platelet reactivity and inflammatory markers.

The new oral anticoagulants (NOACs) reduce stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF), but dabigatran may increase risk of coronary ischemic events for unclear reasons. Thus, this study assessed the effects of dabigatran and rivaroxaban on platelet reactivity and inflammatory markers in patients with non-valvular AF. Patients with non-valvular AF planned to begin treatment with NOACs were included. Seventeen patients were prescribed dabigatran and ten rivaroxaban. Platelet function (as assessed by multiple-electrode aggregometry, Impact-R shear-induced platelet deposition, P-selectin expression and plasma RANTES levels) and high-sensitivity C-reactive protein (hs-CRP) were measured at enrollment (prior to initiation of NOAC treatment) and at least 7 days into treatment with either dabigratran or rivaroxaban. Seventeen patients treated with dabigatran (mean age 69 ± 7 years, 35 % women, mean CHADS2 score 2.6 ± 1.2), and ten patients treated with rivaroxaban (mean age 73 ± 9 years, 20 % women, mean CHADS2 score 2.7 ± 1.6) completed the study. In both groups, there were no significant differences in platelet reactivity between the baseline and on-anticoagulant treatment time-points, as measured by each of the platelet-specific assays. There was a trend towards increased platelet reactivity in response to arachidonic acid from baseline to on-treatment in both groups, probably as a result of aspirin discontinuation in 33 % of patients. No significant differences were noted between baseline and on-treatment in hs-CRP in both anticoagulant groups. Treatment with dabigatran and rivaroxaban does not appear to be associated with changes in markers of platelet reactivity or systemic inflammation.

Cardiac MRI predictors of adverse outcomes in adults with a systemic right ventricle.

AIMS: Predicting risk in individuals with a systemic right ventricle (SRV) remains difficult. We assessed the value of cardiac MRI (CMR) for predicting death, heart transplantation (HT), or need for a ventricular assist device (VAD) in adults with D-transposition of the great arteries (DTGA) post Mustard/Senning and in adults with congenitally corrected transposition of the great arteries (ccTGA) at two large academic centres. METHODS AND RESULTS: Between December 1999 and November 2020, 158 adult patients with an SRV underwent CMR. Indexed right ventricular end-diastolic volume (RVEDVI), indexed right ventricular end-systolic volume (RVESVI), right ventricular ejection fraction (RVEF), and right ventricular mass (RV mass) were determined by a core laboratory. Receiver operating curves, area under the curve (AUC), and cut-points maximizing sensitivity and specificity for the endpoint for each CMR parameter were calculated. Over a median of 8.5 years, 21 patients (13%) met a combined endpoint of HT referral, VAD, or death. Each CMR parameter was significantly associated with the endpoint in both cohorts. The AUCs for RVEDVI, RVESVI, RVEF, and RV mass to predict the endpoint were 0.93, 0.90, 0.73, and 0.84 for DTGA and 0.76, 0.74, 0.71, and 0.74 for ccTGA, respectively. Optimized cut-points for RVEDVI were calculated for DTGA and ccTGA and were 132 and 126 mL/m2 , respectively. RVEDVI cut-points were simplified to 130 mL/m2 for survival analysis, which was significantly associated with survival in both cohorts. CONCLUSIONS: Cardiac MRI parameters are associated with an increased risk of death, HT, or VAD in patients with an SRV and should be considered to facilitate risk stratification.

Outcomes and risk analysis after tricuspid valve surgery for non-Ebstein 2-ventricle congenital tricuspid valve diseases.

Objectives: Tricuspid valve (TV) surgery remains understudied and little data exist describing the surgical indications, outcomes, and prognostic factors for pediatric patients with non-Ebstein 2-ventricle congenital TV lesions. This study aims to describe early and late outcomes of pediatric patients with non-Ebstein congenital TV lesions undergoing isolated TV procedures at a single institution. Methods: All patients who underwent TV surgery for non-Ebstein congenital TV disease between 2006 and 2018 were included. Patients who had missing preoperative data, patients with single-ventricle physiology, congenitally corrected transposition of the great arteries, and patients undergoing TV intervention as part of repair of an atrioventricular canal defect were excluded. The primary end point was the occurrence of TV reintervention or TV regurgitation (TR) ≥ moderate. Results: A total of 85 patients were included. The tricuspid lesion was isolated TR in 80 (94.1%), isolated tricuspid stenosis in 3 (3.5%) and mixed disease in 2 (2.4%) patients. Median age at surgery was 33 years (interquartile range, 12-53 years). TV repair and TV replacement were performed in 66 (77.6%) and 19 (22.4%) patients, respectively. One (1.2%) patient underwent TV reoperation during the same admission. There was no in-hospital mortality. Median follow-up was 3.3 years (interquartile range, 0.1-4.7 years). The overall cumulative incidence of TV reintervention or TR deemed moderate or greater at 1, 3, and 5 years was 3% ± 2%, 11% ± 4%, and 20% ± 8%. In multivariable analysis, age younger than 12 years (P = .04) and mitral valve regurgitation deemed moderate or greater (P = .01) were independent risk factors for TV reintervention or recurrent TR deemed to be moderate or greater at last follow-up. Conclusions: TV surgery in patients with non-Ebstein congenital TV disease can be performed with good outcomes. TV reintervention or TR deemed moderate or greater occurred in 20% of patients on midterm follow-up. Patients younger than age 12 years are at higher risk for recurrent TR or TV reintervention, whereas preoperative MR deemed moderate or greater increases this risk, especially in patients older than age 12 years. There was no difference in outcomes between TV replacement and repair.

Association Between Mitral Annular Calcium and Flail Mitral Leaflet in Degenerative Mitral Valve Disease.

The aim of this study was to assess the association between mitral annular calcium (MAC) and flail mitral leaflets in a cohort of patients with degenerative mitral valve disease. A retrospective study was conducted of consecutive patients with degenerative mitral valve disease who underwent echocardiography at Rabin Medical Center from 2003 to 2012. Special focus was attended to the presence and grade of MAC and characterization of valve pathology (myxomatous vs nonmyxomatous, prolapse vs flail). Patients were excluded if they had undergone previous mitral valve surgery and/or had infective endocarditis. Multivariate logistic regressions were used to control for confounders. The study included 1,912 patients (60.8% men, mean age 63.8 ± 17.4 years) divided into 3 groups: 1,627 (86%) without MAC, 183 (10%) with either mild or moderate MAC, and 94 (5%) with severe MAC. The presence of flail leaflet was 27%, 30%, and 46% in these groups, respectively (p <0.001). After adjustment for age, gender, and co-morbidities, the odd ratio for flail mitral leaflet with severe MAC versus no MAC was 1.76 (95% confidence interval 1.10 to 2.83, p = 0.019). In conclusion, this study demonstrates that degenerative mitral valve disease with severe MAC is significantly associated with flail mitral leaflet.

Response to prasugrel and levels of circulating reticulated platelets in patients with ST-segment elevation myocardial infarction.

OBJECTIVES: The aim of this study was to determine whether response to prasugrel is associated with the proportion of circulating reticulated platelets (RPs) in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Despite better pharmacodynamic properties and clinical efficacy of prasugrel compared with clopidogrel, antiplatelet responses to prasugrel are not uniform. The mechanism of this variability in response is not clear. RPs, young hyperactive forms, are increased during situations of enhanced platelet turnover. METHODS: Patients with STEMI treated with primary percutaneous intervention (PCI) and prasugrel were tested for platelet reactivity using purinergic receptor P2Y, G-protein coupled, 12 (P2Y12) assay and multiple electrode aggregometry (MEA). RP levels were determined using flow cytometry with thiazole orange staining. Tests were performed at 2 to 4 days and 30 days post-PCI. Platelet function was compared by varying levels of RPs, analyzed as continuous (regression analysis) and categorical (tertiles) variables. RESULTS: Sixty-two patients were included (mean age: 57.5 ± 8 years; 21.2% women; 27.7% diabetes). At the early time point, RP levels were strongly correlated with platelet reactivity when evaluated by the P2Y12 assay (Spearman's correlation coefficient: 0.55 for P2Y12 reaction units, -0.49 for percent inhibition) and MEA (Spearman's: 0.50). The upper tertile of RPs displayed higher platelet reactivity compared with the middle and lower tertiles, according to P2Y12 assay and MEA. Similar results with strong correlations between RP and platelet reactivity were noted at 30 days post-PCI. CONCLUSIONS: The proportion of circulating RPs strongly correlates with response to prasugrel in patients with STEMI treated with PCI. High levels of RPs are associated with increased platelet reactivity despite prasugrel treatment.

Tumor lysis syndrome and malignant melanoma.

Tumor lysis syndrome (TLS) is an oncological emergency that results from massive cytolysis of malignant cells with a sudden release of their contents into the systemic circulation. TLS was rarely described in patients with malignant melanoma. In this article, we describe two patients with malignant melanoma who developed this syndrome. In one of them, the syndrome occurred spontaneously, and this is the second description of spontaneous tumor lysis in a patient with melanoma. We reviewed the previous patients with melanoma-induced TLS and discussed the manifestations and the pathophysiology of the syndrome in our patients.

Thrombocytopenia in Staphylococcus aureus bacteremia: risk factors and prognostic importance.

OBJECTIVE: To identify risk factors and outcomes associated with thrombocytopenia at sepsis onset in Staphylococcus aureus bacteremia. PATIENTS AND METHODS: This single-center, retrospective, cohort study consists of all adult patients with a first episode of clinical S aureus bacteremia between April 1, 1988, and September 30, 1994, and between January 1, 1999, and December 31, 2007. Thrombocytopenia was defined as a platelet count less than 150 × 10(9)/L. The primary outcome was 30-day all-cause mortality. Risk factors for 30-day all-cause mortality were identified using univariate and multivariable analyses. Multivariable analysis was conducted using forward step logistic regression analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for risk of death. RESULTS: A total of 1052 patients had clinical S aureus bacteremia. Thrombocytopenia at sepsis onset was present in 235 patients (22.3%). Thrombocytopenia was associated with community-acquired bacteremia, infections caused by methicillin-sensitive S aureus, high-magnitude bacteremia (defined as >4 positive blood cultures [≥ 3 separate positive blood culture sets]), and endocarditis. Patients with thrombocytopenia presented more commonly with severe sepsis reflected by septic shock and acute renal failure. Thirty-day mortality was significantly higher among patients with thrombocytopenia (132/235 [56.2%]) vs those without thrombocytopenia (281/817 [34.4%]; P<.001). Higher mortality was associated with the degree of thrombocytopenia. In multivariable analysis, thrombocytopenia at baseline remained an independent risk factor for 30-day mortality (OR, 2.82; 95% CI, 1.87-4.24). The adjusted association between thrombocytopenia and death remained similar among the 917 patients with monomicrobial bacteremia (OR, 2.88; 95% CI, 1.83-4.53) and the 945 patients who did not die within the first 48 hours (OR, 2.88; 95% CI, 1.87-4.45.). CONCLUSION: We observed a strong association between thrombocytopenia at sepsis onset and all-cause mortality in S aureus bacteremia, possibly related to mechanisms other than sepsis alone.