Long-term impact of myocardial inflammation on quantitative myocardial perfusion-a descriptive PET/MR myocarditis study.

PURPOSE: Whether myocardial inflammation causes long-term sequelae potentially affecting myocardial blood flow (MBF) is unknown. We aimed to assess the effect of myocardial inflammation on quantitative MBF parameters, as assessed by 13N-ammonia positron emission tomography myocardial perfusion imaging (PET-MPI) late after myocarditis. METHODS: Fifty patients with a history of myocarditis underwent cardiac magnetic resonance (CMR) imaging at diagnosis and PET/MR imaging at follow-up at least 6 months later. Segmental MBF, myocardial flow reserve (MFR), and 13N-ammonia washout were obtained from PET, and segments with reduced 13N-ammonia retention, resembling scar, were recorded. Based on CMR, segments were classified as remote (n = 469), healed (inflammation at baseline but no late gadolinium enhancement [LGE] at follow-up, n = 118), and scarred (LGE at follow-up, n = 72). Additionally, apparently healed segments but with scar at PET were classified as PET discordant (n = 18). RESULTS: Compared to remote segments, healed segments showed higher stress MBF (2.71 mL*min-1*g-1 [IQR 2.18-3.08] vs. 2.20 mL*min-1*g-1 [1.75-2.68], p < 0.0001), MFR (3.78 [2.83-4.79] vs. 3.36 [2.60-4.03], p < 0.0001), and washout (rest 0.24/min [0.18-0.31] and stress 0.53/min [0.40-0.67] vs. 0.22/min [0.16-0.27] and 0.46/min [0.32-0.63], p = 0.010 and p = 0.021, respectively). While PET discordant segments did not differ from healed segments regarding MBF and MFR, washout was higher by ~ 30% (p < 0.014). Finally, 10 (20%) patients were diagnosed by PET-MPI as presenting with a myocardial scar but without a corresponding LGE. CONCLUSION: In patients with a history of myocarditis, quantitative measurements of myocardial perfusion as obtained from PET-MPI remain altered in areas initially affected by inflammation. CMR = cardiac magnetic resonance; PET = positron emission tomography; LGE = late gadolinium enhancement.

Percutaneous patent foramen ovale closure during live case demonstrations.

BACKGROUND: Live case demonstrations serve as an educational tool for interventional techniques in cardiology. The aim of this study was to assess the safety and technical success of percutaneous patent foramen ovale (PFO) closure during live case demonstrations. METHODS: All patients who had undergone percutaneous PFO closure with Amplatzer devices during live case demonstrations at our institution were consecutively included in this retrospective analysis. Procedure related events were compared with summary event rates derived from the eight randomized controlled trials (RCTs) investigating PFO closure, as well as with a propensity matched cohort of patients treated under usual conditions. RESULTS: From April 2004 to June 2015, 142 patients underwent percutaneous PFO closure during live demonstrations, mainly for secondary prevention of cryptogenic cerebrovascular events. The interventions were fluoroscopy guided and successful in all but three cases (2%). Minor adverse events occurred in nine patients (6%). Contrast TEE performed at about 6 months showed complete closure in 84%. No significant differences with regard to technical success and major complications rate were found compared to RCTs, except for an increased rate of minor bleeding observed during live case demonstrations (P for difference < 0.001), mainly attributable to concomitant arterial access for incidental coronary angiography performed in 70% of patients. Except for slightly longer procedure duration, no difference was found compared to a matched population treated under usual conditions. CONCLUSION: Percutaneous PFO closure can be performed during live case demonstrations with the same high technical success as during routine cases.

Percutaneous closure of patent foramen ovale in cryptogenic embolism.

BACKGROUND: The options for secondary prevention of cryptogenic embolism in patients with patent foramen ovale are administration of antithrombotic medications or percutaneous closure of the patent foramen ovale. We investigated whether closure is superior to medical therapy. METHODS: We performed a multicenter, superiority trial in 29 centers in Europe, Canada, Brazil, and Australia in which the assessors of end points were unaware of the study-group assignments. Patients with a patent foramen ovale and ischemic stroke, transient ischemic attack (TIA), or a peripheral thromboembolic event were randomly assigned to undergo closure of the patent foramen ovale with the Amplatzer PFO Occluder or to receive medical therapy. The primary end point was a composite of death, nonfatal stroke, TIA, or peripheral embolism. Analysis was performed on data for the intention-to-treat population. RESULTS: The mean duration of follow-up was 4.1 years in the closure group and 4.0 years in the medical-therapy group. The primary end point occurred in 7 of the 204 patients (3.4%) in the closure group and in 11 of the 210 patients (5.2%) in the medical-therapy group (hazard ratio for closure vs. medical therapy, 0.63; 95% confidence interval [CI], 0.24 to 1.62; P=0.34). Nonfatal stroke occurred in 1 patient (0.5%) in the closure group and 5 patients (2.4%) in the medical-therapy group (hazard ratio, 0.20; 95% CI, 0.02 to 1.72; P=0.14), and TIA occurred in 5 patients (2.5%) and 7 patients (3.3%), respectively (hazard ratio, 0.71; 95% CI, 0.23 to 2.24; P=0.56). CONCLUSIONS: Closure of a patent foramen ovale for secondary prevention of cryptogenic embolism did not result in a significant reduction in the risk of recurrent embolic events or death as compared with medical therapy. (Funded by St. Jude Medical; ClinicalTrials.gov number, NCT00166257.).

Intracoronary injection of bone marrow-derived mononuclear cells early or late after acute myocardial infarction: effects on global left ventricular function.

BACKGROUND: Intracoronary administration of autologous bone marrow-derived mononuclear cells (BM-MNC) may improve remodeling of the left ventricle (LV) after acute myocardial infarction. The optimal time point of administration of BM-MNC is still uncertain and has rarely been addressed prospectively in randomized clinical trials. METHODS AND RESULTS: In a multicenter study, we randomized 200 patients with large, successfully reperfused ST-segment elevation myocardial infarction in a 1:1:1 pattern into an open-labeled control and 2 BM-MNC treatment groups. In the BM-MNC groups, cells were administered either early (i.e., 5 to 7 days) or late (i.e., 3 to 4 weeks) after acute myocardial infarction. Cardiac magnetic resonance imaging was performed at baseline and after 4 months. The primary end point was the change from baseline to 4 months in global LV ejection fraction between the 2 treatment groups and the control group. The absolute change in LV ejection fraction from baseline to 4 months was -0.4±8.8% (mean±SD; P=0.74 versus baseline) in the control group, 1.8±8.4% (P=0.12 versus baseline) in the early group, and 0.8±7.6% (P=0.45 versus baseline) in the late group. The treatment effect of BM-MNC as estimated by ANCOVA was 1.25 (95% confidence interval, -1.83 to 4.32; P=0.42) for the early therapy group and 0.55 (95% confidence interval, -2.61 to 3.71; P=0.73) for the late therapy group. CONCLUSIONS: Among patients with ST-segment elevation myocardial infarction and LV dysfunction after successful reperfusion, intracoronary infusion of BM-MNC at either 5 to 7 days or 3 to 4 weeks after acute myocardial infarction did not improve LV function at 4-month follow-up. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00355186.

Impact of tafamidis on myocardial function and CMR tissue characteristics in transthyretin amyloid cardiomyopathy.

AIMS: Tafamidis improves clinical outcomes in transthyretin amyloid cardiomyopathy (ATTR-CM), yet how tafamidis affects cardiac structure and function remains poorly described. This study prospectively analysed the effect of tafamidis on 12-month longitudinal changes in cardiac structure and function by cardiac magnetic resonance (CMR) compared with the natural course of disease in an untreated historic control cohort. METHODS AND RESULTS: ATTR-CM patients underwent CMR at tafamidis initiation and at 12 months. Untreated patients with serial CMRs served as reference to compare biventricular function, global longitudinal strain (GLS), LV mass and extracellular volume fraction (ECV). Thirty-six tafamidis-treated (n = 35; 97.1% male) and 15 untreated patients (n = 14; 93.3% male) with a mean age of 78.3 ± 6.5 and 76.9 ± 6.5, respectively, and comparable baseline characteristics were included. Tafamidis was associated with preserving biventricular function (LVEF (%): 50.5 ± 12 to 50.7 ± 11.5, P = 0.87; RVEF (%): 48.2 ± 10.4 to 48.2 ± 9.4, P = 0.99) and LV-GLS (-9.6 ± 3.2 to -9.9 ± 2.4%; P = 0.595) at 12 months, while a significantly reduced RV-function (50.8 ± 7.3 to 44.2 ± 11.6%, P = 0.028; P (change over time between groups) = 0.032) and numerically worsening LVGLS (-10.9 ± 3.3 to -9.1 ± 2.9%, P = 0.097; P (change over time between groups) = 0.048) was observed without treatment. LV mass significantly declined with tafamidis (184.7 ± 47.7 to 176.5 ± 44.3 g; P = 0.011), yet remained unchanged in untreated patients (163.8 ± 47.5 to 171.2 ± 39.7 g P = 0.356, P (change over time between groups) = 0.027). Irrespective of tafamidis, ECV and native T1-mapping did not change significantly from baseline to 12-month follow-up (P > 0.05). CONCLUSIONS: Compared with untreated ATTR-CM patients, initiation of tafamidis preserved CMR-measured biventricular function and reduced LV mass at 12 months. ECV and native T1-mapping did not change significantly comparable to baseline in both groups.

Prognostic Implications of Clinical and Imaging Diagnostic Criteria for Myocarditis.

BACKGROUND: The European Society of Cardiology (ESC), the American College of Cardiology, the American Heart Association, and expert consensus documents provide different diagnostic criteria for myocarditis. Their overlap and prognostic value have never been compared. OBJECTIVES: This study aims to assess and compare the predictive value of ESC criteria for clinically suspected myocarditis, updated Lake-Louise criteria (LLC), American Heart Association criteria for probable acute myocarditis (pAM), and expert consensus criteria for acute myocarditis (AM) and complicated myocarditis (CM). METHODS: Patients with a clinical suspicion of myocarditis referred for cardiac magnetic resonance were enrolled at 2 centers. Those with any prior cardiomyopathy were excluded. The association of composite outcome events (heart failure hospitalization, recurrent myocarditis, sustained ventricular tachycardia, or death) with ESC diagnostic criteria, LLC, pAM, AM, and CM were compared. RESULTS: Among 1,557 consecutive patients referred for cardiac magnetic resonance with possible myocarditis, 1,050 (62.6% male; 48.9 ± 16.8 years of age) were without an alternative diagnosis. Of those, 938 (89.3%) met ESC criteria for clinically suspected myocarditis, 299 (28.5%) LLC, and 356 (33.9%), 216 (20.6%), and 77 (7.3%) pAM, AM, and CM, respectively. Adverse events occurred in 161 patients (15.3%) during a median follow-up of 3.4 years. The highest annualized event rates (6.6%) were observed in patients meeting LLC, whereas negative ESC criteria indicated excellent prognosis (0.7% annualized event rate). Among all myocarditis definitions, ESC criteria and LLC were the strongest multivariable outcome predictors and had independent and incremental prognostic value (HRadjusted: 3.87; 95% CI: 1.22-12.2; P = 0.021, and HRadjusted: 2.53; 95% CI: 1.83-3.49; P < 0.001, respectively) when adjusted for clinical characteristics. CONCLUSIONS: In a real-world cohort of patients with possible myocarditis, diagnosis was reached in most patients using ESC criteria whereas only approximately one-quarter of patients reached a diagnosis with LLC. The independent prognostic value of ESC-criteria and LLC highlights the complementary role of clinical and CMR-based findings in the diagnosis and risk stratification of myocarditis.

Long-term propensity score-matched comparison of percutaneous closure of patent foramen ovale with medical treatment after paradoxical embolism.

BACKGROUND: Patients with ischemic stroke or transient ischemic attack presumably related to patent foramen ovale (PFO) are at risk for recurrent cerebrovascular events. Differences in long-term clinical outcome were investigated among patients with percutaneous PFO closure and those who received medical treatment. METHODS AND RESULTS: Between 1994 and 2000, 308 consecutive patients with cerebrovascular events presumably related to PFO underwent either percutaneous PFO closure (150 patients) or medical treatment (158 patients). Patients were followed up prospectively for up to 15 years. Seven patients were lost during follow-up. The primary outcome was a composite of stroke, transient ischemic attack, or peripheral embolism. We analyzed 103 propensity score-matched pairs of patients who underwent percutaneous PFO closure or medical treatment. At a median follow-up of 9 years, the primary composite outcome occurred in 11 patients slated to PFO closure (11%) and 22 patients slated to medical treatment (21%; hazard ratio=0.43; 95% confidence interval=0.20-0.94; P=0.033). The treatment effect was driven by a decrease in the risk of transient ischemic attack of 5% versus 14%, respectively (hazard ratio=0.31; 95% confidence interval=0.10-0.94; P=0.039). The risk of all-cause (6% in both groups) and cardiovascular (3% in both groups) mortality appeared to be identical. CONCLUSION: In this long-term observational, propensity score-matched study, percutaneous PFO closure was more effective than medical treatment for the secondary prevention of recurrent cerebrovascular events among patients with PFO-related transient ischemic attack or stroke.

Secondary stroke prevention: patent foramen ovale, aortic plaque, and carotid stenosis.

Stroke is the most debilitating cardiovascular event. It has a variety of causes that may be present simultaneously. In young or otherwise healthy people, the search for a patent foramen ovale (PFO) has become standard. In stroke of the elderly, atherosclerosis and atrial fibrillation are in the foreground but the PFO should not be ignored. The risk of a PFO-related stroke over time is controversial and so is its prevention by device closure. The association of proximal aortic plaques in arteries subtending the brain and stroke is considered strong, ignoring that it is as putative as that of the PFO. Statins can prevent progression of such plaques. Antiplatelet agents in asymptomatic and surgical endarterectomy in symptomatic patients or highly ulcerated lesions are the treatment of choice. Stenting with protection devices was shown competitive in selected patients.

Prognostic Value of Right Ventricular Function in Patients With Suspected Myocarditis Undergoing Cardiac Magnetic Resonance.

BACKGROUND: Risk-stratification of myocarditis is based on functional parameters and tissue characterization of the left ventricle (LV), whereas right ventricular (RV) involvement remains mostly unrecognized. OBJECTIVES: In this study, the authors sought to analyze the prognostic value of RV involvement in myocarditis by cardiac magnetic resonance (CMR). METHODS: Patients meeting the recommended clinical criteria for suspected myocarditis were enrolled at 2 centers. Exclusion criteria were the evidence of coronary artery disease, pulmonary artery hypertension or structural cardiomyopathy. Biventricular ejection fraction, edema according to T2-weighted images, and late gadolinium enhancement (LGE) were linked to a composite end point of major adverse cardiovascular events (MACE), including heart failure hospitalization, ventricular arrhythmia, recurrent myocarditis, and death. RESULTS: Among 1,125 consecutive patients, 736 (mean age: 47.8 ± 16.1 years) met the clinical diagnosis of suspected myocarditis and were followed for 3.7 years. Signs of RV involvement (abnormal right ventricular ejection fraction [RVEF], RV edema, and RV-LGE) were present in 188 (25.6%), 158 (21.5%), and 92 (12.5%) patients, respectively. MACE occurred in 122 patients (16.6%) and was univariably associated with left ventricular ejection fraction (LVEF), LV edema, LV-LGE, RV-LGE, RV edema, and RVEF. In a series of nesting multivariable Cox regression models, the addition of RVEF (HRadj: 0.974 [95% CI: 0.956-0.993]; P = 0.006) improved prognostication (chi-square test = 89.5; P = 0.001 vs model 1; P = 0.006 vs model 2) compared with model 1 including only clinical variables (chi-square test = 28.54) and model 2 based on clinical parameters, LVEF, and LV-LGE extent (chi-square test = 78.93). CONCLUSIONS: This study emphasizes the role of RV involvement in myocarditis and demonstrates the independent and incremental prognostic value of RVEF beyond clinical variables, CMR tissue characterization, and LV function. (Inflammatory Cardiomyopathy Bern Registry [FlamBER]; NCT04774549; CMR Features in Patients With Suspected Myocarditis [CMRMyo]; NCT03470571).

Identification of a multifunctional protein, PhaM, that determines number, surface to volume ratio, subcellular localization and distribution to daughter cells of poly(3-hydroxybutyrate), PHB, granules in Ralstonia eutropha H16.

A two-hybrid approach was applied to screen for proteins with the ability to interact with PHB synthase (PhaC1) of Ralstonia eutropha. The H16_A0141 gene (phaM) was identified in the majority of positive clones. PhaM (26.6 kDa) strongly interacted with PhaC1 and with phasin PhaP5 but not with PhaP1 or other PHB granule-associated proteins. A ΔphaM mutant accumulated only one or two large PHB granules instead of three to six medium-sized PHB granules of the wild type, and distribution of granules to daughter cells was disordered. All three phenotypes (number, size and distribution of PHB granules) were reversed by reintroduction of phaM. Purified PhaM revealed DNA-binding properties in gel mobility shift experiments. Expression of a fusion of the yellow fluorescent protein (eYfp) with PhaM resulted in formation of many small fluorescent granules that were bound to the nucleoid region. Remarkably, an eYfp-PhaP5 fusion localized at the cell poles in a PHB-negative background and overexpression of eYfp-PhaP5 in the wild type conferred binding of PHB granules to the cell poles. In conclusion, subcellular localization of PHB granules in R. eutropha depends on a concerted expression of at least three PHB granule-associated proteins, namely PhaM, PhaP5 and PHB synthase PhaC1.

PHB granules are attached to the nucleoid via PhaM in Ralstonia eutropha.

BACKGROUND: Poly(3-hydroxybutyrate) (PHB) granules are important storage compounds of carbon and energy in many prokaryotes which allow survival of the cells in the absence of suitable carbon sources. Formation and subcellular localization of PHB granules was previously assumed to occur randomly in the cytoplasm of PHB accumulating bacteria. However, contradictionary results on subcellular localization of PHB granules in Ralstonia eutropha were published, recently. RESULTS: Here, we provide evidence by transmission electron microscopy that PHB granules are localized in close contact to the nucleoid region in R. eutropha during growth on nutrient broth. Binding of PHB granules to the nucleoid is mediated by PhaM, a PHB granule associated protein with phasin-like properties that is also able to bind to DNA and to phasin PhaP5. Over-expression of PhaM resulted in formation of many small PHB granules that were always attached to the nucleoid region. In contrast, PHB granules of ∆phaM strains became very large and distribution of granules to daughter cells was impaired. Association of PHB granules to the nucleoid region was prevented by over-expression of PhaP5 and clusters of several PHB granules were mainly localized near the cell poles. CONCLUSION: Subcellular localization of PHB granules is controlled in R. eutropha and depends on the presence and concentrations of at least two PHB granule associated proteins, PhaM and PhaP5.

Diagnostic performance of cardiac magnetic resonance segmental myocardial strain for detecting microvascular obstruction and late gadolinium enhancement in patients presenting after a ST-elevation myocardial infarction.

Background: Microvascular obstruction (MVO) and Late Gadolinium Enhancement (LGE) assessed in cardiac magnetic resonance (CMR) are associated with adverse outcome in patients with ST-elevation myocardial infarction (STEMI). Our aim was to analyze the diagnostic performance of segmental strain for the detection of MVO and LGE. Methods: Patients with anterior STEMI, who underwent additional CMR were enrolled in this sub-study of the CARE-AMI trial. Using CMR feature tracking (FT) segmental circumferential peak strain (SCS) was measured and the diagnostic performance of SCS to discriminate MVO and LGE was assessed in a derivation and validation cohort. Results: Forty-eight STEMI patients (62 ± 12 years old), 39 (81%) males, who underwent CMR (i.e., mean 3.0 ± 1.5 days) after primary percutaneous coronary intervention (PCI) were included. All patients presented with LGE and in 40 (83%) patients, MVO was additionally present. Segments in all patients were visually classified and 146 (19%) segments showed MVO (i.e., LGE+/MVO+), 308 (40%) segments showed LGE and no MVO (i.e., LGE+/MVO-), and 314 (41%) segments showed no LGE (i.e., LGE-). Diagnostic performance of SCS for detecting MVO segments (i.e., LGE+/MVO+ vs. LGE+/MVO-, and LGE-) showed an AUC = 0.764 and SCS cut-off value was -11.2%, resulting in a sensitivity of 78% and a specificity of 67% with a positive predictive value (PPV) of 30% and a negative predictive value (NPV) of 94% when tested in the validation group. For LGE segments (i.e., LGE+/MVO+ and LGE+/MVO- vs. LGE-) AUC = 0.848 and SCS with a cut-off value of -13.8% yielded to a sensitivity of 76%, specificity of 74%, PPV of 81%, and NPV of 70%. Conclusion: Segmental strain in STEMI patients was associated with good diagnostic performance for detection of MVO+ segments and very good diagnostic performance of LGE+ segments. Segmental strain may be useful as a potential contrast-free surrogate marker to improve early risk stratification in patients after primary PCI.

Patent foramen ovale may be causal for the first stroke but unrelated to subsequent ischemic events.

BACKGROUND AND PURPOSE: Studies with very long follow-up are scarce in patients with cryptogenic stroke and patent foramen ovale (PFO). Little is known about the etiology of recurrent cerebrovascular events (CVE) in PFO patients. METHODS: We collected information on recurrent CVE in 308 patients with cryptogenic stroke and PFO and sought to determine concurrent stroke causes that had emerged or been newly detected since the index event. One hundred fifty-eight patients received aspirin (48%), clopidogrel (2%), or oral anticoagulants (50%; medical group). One hundred fifty patients underwent percutaneous PFO closure (closure group). RESULTS: Mean age at index event was 50 years (SD 13). In 33% of patients, the index stroke or transient ischemic attack was preceded by at least 1 CVE. Mean follow-up was 8.7±4.0 years. During follow-up, 32 recurrent CVE (13 strokes and 19 transient ischemic attacks) occurred in the medical and 16 recurrent CVE (8 strokes and 8 transient ischemic attacks) in the closure group. Concurrent etiologies were identified for 12 recurrent CVE in the medical group (38%): large artery disease (9%), small artery disease (6%), cardioembolism (13%), cerebral vasculitis (3%), and antiphospholipid-antibody-syndrome (6%). In the closure group, 7 recurrent CVE had a concurrent etiology (44%): large artery disease (6%), small artery disease (19%), cardioembolism (13%), and thrombophilic disorder (6%). The frequency of concurrent etiologies did not differ between patients with recurrent CVE under medical treatment and those undergoing PFO closure (P=0.68). CONCLUSIONS: Concurrent etiologies are identified for more than one third of recurrent ischemic events in patients with cryptogenic stroke, casting doubt on the sole causal role of PFO.

Figulla PFO occluder versus Amplatzer PFO occluder for percutaneous closure of patent foramen ovale.

BACKGROUND: Percutaneous closure of patent foramen ovale (PFO) has been shown safe and feasible using several devices. The Occlutech Figulla single layer PFO Occluder (FPO) constitutes an alternative to the Amplatzer PFO Occluder (APFO). OBJECTIVES: We report our experience with both devices in a single-center case-control study. METHODS: Twenty patients undergoing percutaneous PFO closure using an FPO for secondary prevention of paradoxical embolism or diving were blindly matched with 20 patients receiving an APFO during the same time period. Contrast transesophageal echocardiography (TEE) was performed 6 months after device implantation to assess for residual shunting and device-associated thrombus. RESULTS: Patient baseline characteristics were well matched by study design. Procedural success was 95% with FPO vs. 100% for APFO (P = 1.0), with 3 (15%) peri-procedural complications with FPO vs. none with APFO (P = 0.24). These comprised one asymptomatic device embolization in the descending aorta with percutaneous retrieval, one transient ischemic attacks, and one suspected device endocarditis. Contrast TEE at 6 months showed significantly more residual shunts in the FPO-group (39% vs. 0%; P = 0.01). Two FPO patients with a moderate residual shunt underwent implantation of a second device (APFO 25 mm) vs. none in the APFO group (P = 0.48). No thrombi were observed in either group. During 1.7 ± 0.7 years of follow-up, no death or recurrent embolic event occurred. CONCLUSIONS: According to this single-center case-control study, PFO closure with the FPO appears less efficacious than with the APFO.

Right ventricular systolic function assessment: rank of echocardiographic methods vs. cardiac magnetic resonance imaging.

AIMS: Right ventricular (RV) systolic function is prognostically important, but its assessment by echocardiography remains challenging, in part because of the multitude of available measurement methods. The purpose of this prospective study was to rank these methods against the reference of RV ejection fraction (EF) as obtained in a broad clinical population by magnetic resonance imaging (MRI). METHODS AND RESULTS: Two hundred and twenty-three individuals were included in the study. The following seven Doppler echocardiographic parameters were tested using receiver operating characteristic (ROC) analysis for their accuracy to distinguish between normal and moderately impaired RVEF by MRI (RVEF cut-off 50%), respectively, between moderately and severely reduced RVEF (cut-off 30%): RV fractional area and fractional long-axis change (FLC), RV myocardial performance index (MPI), tricuspid annular peak systolic excursion, Doppler tissue imaging-derived isovolumic acceleration and peak systolic velocity (S') at the lateral tricuspid annulus, and strain at the lateral free wall as obtained by speckle-tracking echocardiography. Survival analysis was performed. All seven Doppler echocardiographic parameters correlated significantly with RVEF by MRI (range between 5 and 85%). RVEF <50% was best detected by S' < 11 cm/s: area under the ROC curve 0.779 (95% confidence interval 0.716-0.843), sensitivity 0.740, and specificity 0.753. RVEF ≤30% was best detected by MPI > 0.50: area under the ROC curve 0.948 (95% confidence interval 0.906-0.991), sensitivity 0.947, and specificity 0.852. The Kaplan-Meier analysis revealed reduced cumulative survival among patients with RVEF ≤30% (P = 0.0003). CONCLUSION: A systolic long-axis peak velocity of <11 cm/s at the lateral tricuspid annulus most accurately detects moderately impaired RVEF as obtained by MRI; severely reduced RVEF ≤30% is best detected by RV MPI at a value of >0.50.

Facilitation Through Aggrastat or Cangrelor Bolus and Infusion Over PrasugreL: a MUlticenter Randomized Open-label Trial in PatientS with ST-elevation Myocardial InFarction Referred for PrimAry PercutaneouS InTERvention (FABOLUS FASTER) Trial: Design and Rationale : The FABOLUS FASTER Trial.

Antithrombotic therapy is a critical component of the management of ST-elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PCI). Rapid and profound inhibition of platelet reactivity has been shown to mitigate the ischemic risks and improve myocardial salvage. High residual platelet reactivity (HRPR) has been reported up to 4 or 6 h after loading dose of prasugrel or ticagrelor; therefore, multiple alternative strategies, including crushed or chewed oral tables or intravenous agents, have been investigated to provide a more rapid and sustained inhibition of platelet function and bridge the initial treatment gap. The FABOLUS FASTER is the first investigator-initiated, multicentre, open-label, prospective, randomized study to directly compare the pharmacodynamics effects of cangrelor, tirofiban, chewed or integer prasugrel. This study will add new insights in the management of antiplatelet therapy in patients with STEMI undergoing primary PCI and might be hypothesis-generating for future clinical trials in this field. The trial is registered on clinicaltrials.gov NCT02978040, and EudraCT 2017-001065-24.

Cell-based therapy for myocardial repair in patients with acute myocardial infarction: rationale and study design of the SWiss multicenter Intracoronary Stem cells Study in Acute Myocardial Infarction (SWISS-AMI).

BACKGROUND: Recent studies report that intracoronary administration of autologous bone marrow mononucleated cells (BM-MNCs) may improve remodeling of the left ventricle after acute myocardial infarction (AMI). Subgroup analysis suggest that early treatment between days 4 and 7 after AMI is probably most effective; however, the optimal time point of intracoronary cell administration has never been addressed in clinical trials. Furthermore, reliable clinical predictors are lacking for identifying patients who are thought to have most benefit from cellular therapy. STUDY DESIGN: In a multicenter trial, 192 patients with AMI successfully treated by percutaneous coronary intervention (PCI) of the infarct-related artery will be randomized in a 1:1:1 pattern to 1 control and 2 BM-MNC treatment groups. The control group will be treated with state-of-the-art medical management. The treatment groups will receive intracoronary administration of autologous BM-MNC at 5 to 7 days or 3 to 4 weeks after the initial event, respectively. Left ventricular function as well as scar size, transmural extension, and regional wall motion score will be assessed by cardiac magnetic resonance (CMR) studies at baseline and after 4 and 12 months. METHODS: Fifty milliliters of bone marrow will be harvested by aspiration from the iliac crest and then carried by courier to a centralized cell processing facility. The mononucleated cell fraction will be isolated by density gradient centrifugation, washed, and resuspended in 10 mL of injection medium. The cells will be characterized by fluorescence-activated cell sorting analysis and tested for sterility and potency both "in vitro" and "in vivo." Bone marrow MNC will then be reinfused directly in the infarct-related coronary artery. END POINTS: The primary end point is the change in global left ventricular (LV) ejection fraction by CMR at 4 months as compared to baseline. Comparisons will then be made between each of the prespecified therapy subgroups (early and late after AMI) and the control group. Secondary end points include change in infarct size, change in regional myocardial thickness, and wall motion at 4 and 12 months compared to baseline. Infarct extension (size and transmural extension), time delay to PCI, and coronary flow characteristics after PCI will be assessed as potential predictors of LV remodeling and change after cell therapy. Major adverse cardiac events (MACE) (death, myocardial infarction, coronary revascularization, rehospitalization for heart failure) will be assessed at 4, 12, and 24 months and time to MACE will be estimated. DISCUSSION: With the present study, we aim to determine the optimal time point of intracoronary administration of autologous BM-MNC after AMI on LV remodeling.

Percutaneous closure of patent foramen ovale for migraine headaches refractory to medical treatment.

BACKGROUND: Patent foramen ovale (PFO) has been linked to migraine, and several retrospective studies reported an improvement in migraine prevalence or frequency after PFO closure for other reasons, mostly for secondary prevention of paradoxical embolism or following diving accidents. We investigated the outcome of patients undergoing PFO closure solely for migraine headaches refractory to medical treatment. METHODS: Seventeen patients (age 44 +/- 12 years; 76% female; one atrial septal aneurysm) underwent percutaneous PFO closure using the Amplatzer PFO Occluder (AGA Medical Corporation, Golden Valley, MN). An 18-mm device was used in two patients, a 25-mm device in 13, and a 35-mm device in two. The interventions were solely guided by fluoroscopy, without intraprocedural echocardiography. RESULTS: All implantation procedures were successful. There were no peri-procedural complications. Contrast transesophageal echocardiography after Valsalva maneuver at 6 months showed complete PFO closure in 16 patients (94%), whereas a minimal residual shunt persisted in one (6%). During 2.7 +/- 1.5 years of follow-up, no deaths and no embolic events occurred. After PFO closure, migraine headaches disappeared in four patients (24%), and improved in eight additional patients (47%). Three patients (18%) reported a decrease of their headaches by 75%, three patients (18%) a decrease of 50%, and two patients (12%) a decrease of 25%, while headaches remained unchanged in five patients (29%). No patient experienced worsening headaches. Moreover, the prevalence of migraine with aura decreased from 82 to 24% (P = 0.002). CONCLUSIONS: These results suggest that percutaneous PFO closure durably alters the spontaneous course of shunt associated migraine.

Amplatzer patent foramen ovale occluder: safety and efficacy.

INTRODUCTION: The patent foramen ovale (PFO) is a common anatomical variant in humans (prevalence 25%). Most often asymptomatic, it may engender paradoxically embolic strokes, myocardial infarctions, or visceral or peripheral ischemia. It is causatively related to migraine, positional or exertional hypoxemia with dyspnea, diving incidents, high altitude edema, and sleep apnea. Percutaneous closure of atrial septal defects was first performed in the seventies. A dedicated PFO occluder (Amplatzer PFO Occluder) was first used on 10 September 1997 by Kurt Amplatz and Bernhard Meier. Since, percutaneous PFO closure has evolved into one of the most common and the simplest and safest catheter-based intervention in adult cardiology. Randomized studies have proved its benefit for prevention of recurrent ischemic events (particularly strokes) in patients without competing stroke etiology. There are also supportive clinical data for PFO closure in other situations. Areas covered: The Amplatzer PFO Occluder, the first, most implanted, and best-studied PFO occluder, is reviewed, presenting implantation technique, possible complications, and pertinent scientific data of efficacy and safety. Expert commentary: Percutaneous PFO closure has grown to one of the most common procedures in interventional cardiology. Implantation of the Amplatzer PFO Occluder is simple, safe, and effective.

Time-Dependent Myocardial Necrosis in Patients With ST-Segment-Elevation Myocardial Infarction Without Angiographic Collateral Flow Visualized by Cardiac Magnetic Resonance Imaging: Results From the Multicenter STEMI-SCAR Project.

Background Acute complete occlusion of a coronary artery results in progressive ischemia, moving from the endocardium to the epicardium (ie, wavefront). Dependent on time to reperfusion and collateral flow, myocardial infarction ( MI ) will manifest, with transmural MI portending poor prognosis. Late gadolinium enhancement cardiac magnetic resonance imaging can detect MI with  high diagnostic accuracy. Primary percutaneous coronary intervention is the preferred reperfusion strategy in patients with ST -segment-elevation MI with <12 hours of symptom onset. We sought to visualize time-dependent necrosis in a population with ST -segment-elevation MI by using late gadolinium enhancement cardiac magnetic resonance imaging (STEMI-SCAR project). Methods and Results ST -segment-elevation MI patients with single-vessel disease, complete occlusion with TIMI (Thrombolysis in Myocardial Infarction) score 0, absence of collateral flow (Rentrop score 0), and symptom onset <12 hours were consecutively enrolled. Using late gadolinium enhancement cardiac magnetic resonance imaging, the area at risk and infarct size, myocardial salvage index, transmurality index, and transmurality grade (0-50%, 51-75%, 76-100%) were determined. In total, 164 patients (aged 54±11 years, 80% male) were included. A receiver operating characteristic curve (area under the curve: 0.81) indicating transmural necrosis revealed the best diagnostic cutoff for a symptom-to-balloon time of 121 minutes: patients with >121 minutes demonstrated increased infarct size, transmurality index, and transmurality grade (all P<0.01) and decreased myocardial salvage index ( P<0.001) versus patients with symptom-to-balloon times ≤121 minutes. Conclusions In MI with no residual antegrade and no collateral flow, immediate reperfusion is vital. A symptom-to-balloon time of >121 minutes causes a high grade of transmural necrosis. In this pure ST -segment-elevation MI population, time to reperfusion to salvage myocardium was less than suggested by current guidelines.