Cardiovascular Magnetic Resonance Imaging in Familial Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is a common cause of non-ischaemic heart failure, conferring high morbidity and mortality, including sudden cardiac death due to systolic dysfunction or arrhythmic sudden death. Within the DCM cohort exists a group of patients with familial disease. In this article we review the pathophysiology and cardiac imaging findings of familial DCM, with specific attention to known disease subtypes. The role of advanced cardiac imaging cardiovascular magnetic resonance is still accumulating, and there remains much to be elucidated. We discuss its potential clinical roles as currently known, with respect to diagnostic utility and risk stratification. Advances in such risk stratification may help target pharmacological and device therapies to those at highest risk.

Arrhythmic effects of Epac-mediated ryanodine receptor activation in Langendorff-perfused murine hearts are associated with reduced conduction velocity.

Recent papers have attributed arrhythmic substrate in murine RyR2-P2328S hearts to reduced action potential (AP) conduction velocities (CV), reflecting acute functional inhibition and/or reduced expression of sodium channels. We explored for acute effects of direct exchange protein directly activated by cAMP (Epac)-mediated ryanodine receptor-2 (RyR2) activation on arrhythmic substrate and CV. Monophasic action potential (MAP) recordings demonstrated that initial steady (8 Hz) extrinsic pacing elicited ventricular tachycardia (VT) in 0 of 18 Langendorff-perfused wild-type mouse ventricles before pharmacological intervention. The Epac activator 8-CPT (8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate) (VT in 1 of 7 hearts), and the RyR2 blocker dantrolene, either alone (0 of 11) or with 8-CPT (0 of 9) did not then increase VT incidence (P>.05). Both progressively increased pacing rates and programmed extrasystolic (S2) stimuli similarly produced no VT in untreated hearts (n=20 and n=9 respectively). 8-CPT challenge then increased VT incidences (5 of 7 and 4 of 8 hearts respectively; P<.05). However, dantrolene, whether alone (0 of 10 and 1 of 13) or combined with 8-CPT (0 of 10 and 0 of 13) did not increase VT incidence relative to those observed in untreated hearts (P>.05). 8-CPT but not dantrolene, whether alone or combined with 8-CPT, correspondingly increased AP latencies (1.14±0.04 (n=7), 1.04±0.03 (n=10), 1.09±0.05 (n=8) relative to respective control values). In contrast, AP durations, conditions for 2:1 conduction block and ventricular effective refractory periods remained unchanged throughout. We thus demonstrate for the first time that acute RyR2 activation reversibly induces VT in specific association with reduced CV.

p.Y1449C SCN5A mutation associated with overlap disorder comprising conduction disease, Brugada syndrome, and atrial flutter.

Mutations in the SCN5A gene, which encodes the cardiac sodium channel, have been associated with cardiac arrhythmia syndromes and conduction disease. Specific SCN5A mutations had initially been considered to cause specific phenotypes. More recently, some SCN5A mutations have been associated with overlap syndromes, characterized by phenotypic heterogeneity within and between mutation carriers. Here we report and associate the presence of the p.Y1449C SCN5A mutation in a single family with a spectrum of cardiac phenotypes including conduction disease, Brugada syndrome and atrial arrhythmias, for the first time to our knowledge.

Considering alternatives to transcatheter heart valves for managing patients with severe aortic valve stenosis.

INTRODUCTION: Transcatheter aortic valve implantation (TAVI) is becoming the standard of care for severe symptomatic aortic stenosis (AS). Yet, some patients with AS are not indicated/eligible for TAVI. Several noninvasive, catheter-based or surgical alternatives exist, and other therapeutic options are emerging. AREAS COVERED: This review provides an overview of non-TAVI options for severe AS. Non-invasive, transcatheter, and alternative surgical strategies are discussed, emphasizing their backgrounds, techniques, and outcomes. EXPERT OPINION: Alternative therapies to TAVI, whether device-based or non-device-based, continue to evolve or emerge and provide either alternative treatments or a bridge to TAVI, for patients not meeting indications for, or having contraindications to TAVI.Although TAVI and SAVR are the current dominant therapies, there are still some patients that could benefit in the future from other alternatives.Data on alternative options for such patients are scarce. Many advantages and disadvantages arise when selecting a specific treatment strategy for individual patients.Head-to-head comparison studies could guide physicians toward better patient selection and procedural planning. Awareness of therapeutic options, indications, techniques, and outcomes should enable heart teams to achieve optimized patient selection. Furthermore, it can increase the use of these alternatives to optimize the management of AS among different patient populations.

Negative chronotropic effects and coronary ischaemic abnormalities following thalidomide therapy.

The severe teratogenic side effects of thalidomide led to its well-publicized withdrawal in the 1970s, but as it is cautiously being reintroduced into clinical use, new adverse effects are being described. A 65-year-old male with multiple myeloma received chemotherapy which included cyclophosphamide, thalidomide and dexamethasone. Whilst on this treatment he experienced severe chest pain leading to an acute hospital admission complicated by significant bradycardia with sinus pauses of 7 s, necessitating temporary right ventricular pacing. Despite correction of the bradycardia with temporary pacing, he experienced further episodes of chest pain, during which an ECG (with the pacemaker briefly switched off) showed ST elevation in the inferior leads along with runs of non-sustained ventricular tachycardia. Emergency coronary angiography demonstrated unobstructed coronary arteries. Due to ST elevation in the absence of flow-limiting coronary disease his presentation was presumed to be due to intermittent coronary artery spasm. He was started on sustained-release nifedipine without any beta-blockers and further thalidomide therapy was omitted. On this pharmacological therapy, over a period of 24 months, there were no further recurrences of any cardiac symptoms. To our knowledge there have been no previous reports of coronary artery spasm associated with the use of thalidomide. The precise mechanism remains undefined, with several plausible hypothetical pathways which we discuss. We discuss various mechanisms including autonomic, autocoid and paracrine modes of action that may underlie cardiac side effects of thalidomide. We report coronary spasm in addition to bradycardia as cardiac side effects that cardiologists and oncologists need to be alert to.

The Use and Efficacy of FFR-CT: Real-World Multicenter Audit of Clinical Data With Cost Analysis.

BACKGROUND: Fractional flow reserve-computed tomography (FFR-CT) is endorsed by UK and U.S. chest pain guidelines, but its clinical effectiveness and cost benefit in real-world practice are unknown. OBJECTIVES: The purpose of this study was to audit the use of FFR-CT in clinical practice against England's National Institute for Health and Care Excellence guidance and assess its diagnostic accuracy and cost. METHODS: A multicenter audit was undertaken covering the 3 years when FFR-CT was centrally funded in England. For coronary computed tomographic angiograms (CCTAs) submitted for FFR-CT analysis, centers provided data on symptoms, CCTA and FFR-CT findings, and subsequent management. Audit standards included using FFR-CT only in patients with stable chest pain and equivocal stenosis (50%-69%). Diagnostic accuracy was evaluated against invasive FFR, when performed. Follow-up for nonfatal myocardial infarction and all-cause mortality was undertaken. The cost of an FFR-CT strategy was compared to alternative stress imaging pathways using cost analysis modeling. RESULTS: A total of 2,298 CCTAs from 12 centers underwent FFR-CT analysis. Stable chest pain was the main symptom in 77%, and 40% had equivocal stenosis. Positive and negative predictive values of FFR-CT were 49% and 76%, respectively. A total of 46 events (2%) occurred over a mean follow-up period of 17 months; FFR-CT (cutoff: 0.80) was not predictive. The FFR-CT strategy costs £2,102 per patient compared with an average of £1,411 for stress imaging. CONCLUSIONS: In clinical practice, the National Institute for Health and Care Excellence criteria for using FFR-CT were met in three-fourths of patients for symptoms and 40% for stenosis. FFR-CT had a low positive predictive value, making its use potentially more expensive than conventional stress imaging strategies.

Herceptin-Mediated Cardiotoxicity: Assessment by Cardiovascular Magnetic Resonance.

Herceptin (trastuzumab) is a recombinant, humanized, monoclonal antibody that targets the human epidermal growth factor receptor 2 (HER2) and is used in the treatment of HER2-positive breast and gastric cancers. However, it carries a risk of cardiotoxicity, manifesting as left ventricular (LV) systolic dysfunction, conventionally assessed for by transthoracic echocardiography. Clinical surveillance of cardiac function and discontinuation of trastuzumab at an early stage of LV systolic dysfunction allow for the timely initiation of heart failure drug therapies that can result in the rapid recovery of cardiac function in most patients. Often considered the reference standard for the noninvasive assessment of cardiac volume and function, cardiac magnetic resonance (CMR) imaging has superior reproducibility and accuracy compared to other noninvasive imaging modalities. However, due to limited availability, it is not routinely used in the serial assessment of cardiac function in patients receiving trastuzumab. In this article, we review the diagnostic and prognostic role of CMR in trastuzumab-mediated cardiotoxicity.

Valvular Cardiomyopathy: The Value of Cardiovascular Magnetic Resonance Imaging.

Cardiovascular magnetic resonance (CMR) imaging has had a vast impact on the understanding of a wide range of disease processes and pathophysiological mechanisms. More recently, it has contributed significantly to the diagnosis and risk stratification of patients with valvular heart disease. With its increasing use, CMR allows for a detailed, reproducible, qualitative, and quantitative evaluation of left ventricular volumes and mass, thereby enabling assessment of the haemodynamic impact of a valvular lesion upon the myocardium. Postprocessing of the routinely acquired images with feature tracking CMR methodology can give invaluable information about myocardial deformation and strain parameters that suggest subclinical ventricular impairment that remains undetected by conventional measures such as the ejection fraction (EF). T1 mapping and late gadolinium enhancement (LGE) imaging provide deep myocardial tissue characterisation that is changing the approach towards risk stratification of patients as an increasing body of evidence suggests that the presence of fibrosis is related to adverse events and prognosis. This review summarises the current evidence regarding the utility of CMR in the left ventricular assessment of patients with aortic stenosis or mitral regurgitation and its value in diagnosis, risk stratification, and management.

Left ventricular T1-mapping in diastole versus systole in patients with mitral regurgitation.

Cardiovascular magnetic resonance T1-mapping enables myocardial tissue characterisation, and is capable of quantifying both intracellular and extracellular volume. T1-mapping is conventionally performed in diastole, however, we hypothesised that systolic readout would reduce variability due to a reduction in myocardial blood volume. This study investigated whether T1-mapping in systole alters T1 values compared to diastole and whether reproducibility alters in atrial fibrillation compared to sinus rhythm. We prospectively identified 103 consecutive patients recruited to the Mitral FINDER study who had T1 mapping in systole and diastole. These patients had moderate or severe mitral regurgitation and a high incidence of ventricular dilatation and atrial fibrillation. T1, ECV and goodness-of-fit (R2) values of the T1 times were calculated offline using Circle cvi42 and in house-developed software. Systolic T1 mapping was associated with fewer myocardial segments being affected by artefact compared to diastolic T1 mapping [217/2472 (9%) vs 515/2472 (21%)]. Mean native T1 values were not significantly different when measured in systole and diastole (985 ± 26 ms vs 988 ± 29 respectively; p = 0.061) and mean post-contrast values showed similar good agreement (462 ± 32 ms vs 459 ± 33 respectively, p = 0.052). No clinically significant differences in ECV, native T1 and post-contrast T1 were identified between diastolic and systolic T1 maps in males versus females, or in patients with permanent atrial fibrillation versus sinus rhythm. A statistically significant improvement in R2 value was observed with systolic over diastolic T1 mapping in all analysed maps (n = 411) (96.2 ± 1.4% vs 96.0 ± 1.4%; p < 0.001) and in subgroup analyses [Sinus rhythm: 96.1 ± 1.4 vs 96.3 ± 1.4 (n = 327); p < 0.001. AF: 95.5 ± 1.3 vs 95.9 ± 1.2 (n = 80); p < 0.001] [Males: 95.8 ± 1.4 vs 96.1 ± 1.3 (n = 264); p < 0.001; Females: 96.2 ± 1.3 vs 96.4 ± 1.4 (n = 143); p = 0.009]. In conclusion, myocardial T1 mapping is associated with similar T1 and ECV values in systole and diastole. Furthermore, systolic acquisition is less prone to gating artefact in arrhythmia.

A Longitudinal Study of Mitral Regurgitation Detected after Acute Myocardial Infarction.

BACKGROUND: Mitral regurgitation (MR) is common following myocardial infarction (MI). However, the subsequent trajectory of MR, and its impact on long-term outcomes are not well understood. This study aimed to examine the change in MR severity and associated clinical outcomes following MI. METHODS: Records of patients admitted to a single centre between 2016 and 2017 with acute MI treated by percutaneous coronary intervention (PCI) were retrospectively examined. RESULTS: 294/1000 consecutive patients had MR on baseline (pre-discharge) transthoracic echocardiography (TTE), of whom 126 (mean age: 70.9 ± 11.4 years) had at least one follow-up TTE. At baseline, most patients had mild MR (n = 94; 75%), with n = 30 (24%) moderate and n = 2 (2%) severe MR. Significant improvement in MR was observed at the first follow-up TTE (median 9 months from baseline; interquartile range: 3-23), with 36% having reduced severity, compared to 10% having increased MR severity (p < 0.001). Predictors of worsening MR included older age (mean: 75.2 vs. 66.7 years; p = 0.003) and lower creatinine clearance (mean: 60 vs. 81 mL/min, p = 0.015). Change in MR severity was significantly associated with prognosis: 16% with improving MR reached the composite endpoint of death or heart failure hospitalisation at 5 years, versus 44% (p = 0.004) with no change, and 59% (p < 0.001) with worsening MR. CONCLUSIONS: Of patients with follow-up TTE after MI, MR severity improved from baseline in approximately one-third, was stable in around half, with the remainder having worsening MR. Patients with persistent or worsening MR had worse clinical outcomes than those with improving MR.

Utility of Non-invasive Cardiac Imaging Assessment in Coronavirus Disease 2019.

Coronavirus disease 2019 (COVID-19) was initially regarded as a disease of the lungs, which manifests as an acute respiratory illness and pneumonia, although more recently cardiac complications have been well-characterised. Serological cardiac biomarkers have been used to define acute myocardial injury, with significant elevation of high-sensitivity cardiac troponin (hs-cTn) associated with poor prognosis. Accordingly, 20-25% patients with acute myocardial injury (as defined by an elevated hs-cTn greater than the 99th percentile) have clinical signs of heart failure and increased mortality. An important outstanding clinical question is how best to determine the extent and nature of cardiac involvement in COVID-19. Non-invasive cardiac imaging has a well-established role in assessing cardiac structure and function in a wide range of cardiac diseases. It offers the potential to differentiate between direct and indirect COVID-19 effects upon the heart, providing incremental diagnostic and prognostic utility beyond the information yielded by elevated cardiac biomarkers in isolation. This review will focus on the non-invasive imaging assessment of cardiac involvement in COVID-19.

Impact of Right Ventricular Dysfunction on Mortality in Patients Hospitalized With COVID-19, According to Race.

BACKGROUND: Epidemiologic studies suggest that Black, Asian, and minority ethnic (BAME) patients may be at risk of worse outcomes from coronavirus disease-2019 (COVID-19), but the pathophysiological drivers for this association are unknown. This study sought to investigate the relationship between findings on echocardiography, mortality, and race in COVID-19 pneumonia. METHODS: This was a multicentre, retrospective, observational study including 164 adults (aged 61 ± 13 years; 78% male; 36% BAME) hospitalized with COVID-19 undergoing echocardiography between March 16 and May 9, 2020 at 3 days (interquartile range 2-5) from admission. The primary outcome was all-cause mortality. RESULTS: After a median follow-up of 31 days (interquartile range 14-42 days), 66 (40%) patients had died. The right ventricle was dilated in 62 (38%) patients, and 58 (35%) patients had right ventricular (RV) systolic dysfunction. Only 2 (1%) patients had left ventricular (LV) dilatation, and 133 (81%) had normal or hyperdynamic LV systolic function. Reduced tricuspid annulus planar systolic excursion was associated with elevated D-dimer (ρ = -0.18, P = 0.025) and high-sensitivity cardiac Troponin (ρ = -0.30, P < 0.0001). Reduced RV systolic function (hazard ratio 1.80; 95% confidence interval, 1.05-3.09; P = 0.032) was an independent predictor of all-cause mortality after adjustment for demographic and clinical risk factors. Comparing white and BAME individuals, there were no differences in echocardiography findings, biomarkers, or mortality. CONCLUSIONS: In patients hospitalized with COVID-19 pneumonia, reduced RV systolic function is prevalent and associated with all-cause mortality. There is, however, no racial variation in the early findings on echocardiography, biomarkers, or mortality.

CONTEXTE: Des études épidémiologiques suggèrent que les patients noirs, asiatiques et appartenant à des minorités ethniques (BAME) auraient un risque accru d'aggravation de la maladie à coronavirus 2019 (COVID-19), mais les facteurs physiopathologiques de cette association sont inconnus. Cette étude a cherché à étudier la relation entre les données d'échocardiographie, de mortalité, de l'origine ethnique avec la pneumonie associée à la COVID-19. MÉTHODES: Il s'agit d'une étude observationnelle rétrospective multicentrique portant sur 164 adultes (âgés de 61 ± 13 ans; 78 % d'hommes; 36 % de BAME) hospitalisés pour la COVID-19 et soumis à une échocardiographie entre le 16 mars et le 9 mai 2020, trois jours (écart interquartile 2-5) après leur admission. Le critère principal d'évaluation était la mortalité, toutes causes confondues. RÉSULTATS: Après un suivi médian de 31 jours (intervalle interquartile 14-42 jours), 66 (40 %) patients sont décédés. Le ventricule droit était dilaté chez 62 (38 %) des patients, et 58 (35 %) patients présentaient une dysfonction systolique du ventricule droit (VD). Seuls deux (1 %) patients présentaient une dilatation du ventricule gauche (VG), et 133 (81 %) avaient une fonction systolique VG normale ou en état hyperdynamique. Une réduction du déplacement systolique de l'anneau tricuspide a été associée à un taux de D-dimère élevé (ρ = -0,18, P = 0,025) et à une Troponine cardiaque de haute sensibilité (ρ = -0,30, P < 0,0001). Une fonction systolique VD réduite (rapport de risque de 1,80; intervalle de confiance à 95 %, 1,05-3,09 ; P = 0,032) était un facteur prédicteur indépendant pour la mortalité, toutes causes confondues, après ajustement pour les facteurs de risque démographiques et cliniques. En comparant les individus blancs et BAME, aucune différence n'a été constatée concernant les résultats d'échocardiographie, les biomarqueurs ou la mortalité. CONCLUSIONS: Chez les patients hospitalisés pour une pneumonie liée à la COVID-19, une réduction de la fonction systolique VD est apparue comme prévalente et associée à la mortalité, toutes causes confondues. Il n'y a cependant aucune influence de l'ethnicité en rapport avec les premiers résultats d'échocardiographie, des biomarqueurs ou de la mortalité.

Remodelling elective hospital services in the COVID-19 era - designing the new normal.

The provision of elective clinical services has decreased during the initial phase of the coronavirus disease 2019 (COVID-19) pandemic to enable hospitals to focus on acute illness. Any end to the pandemic through widespread vaccination, effective treatment or development of herd immunity may be years away. Until then, hospitals will need to resume treating other diseases while also attempting to eradicate transmission of COVID-19 within the healthcare setting. In this article we suggest six major themes which could affect the design and delivery of elective clinical services: hospital avoidance, separation of high- and low-risk groups, screening, maintenance of adequate infection control, and new ways of working.

Correction to: Restitution metrics in Brugada syndrome: a systematic review and meta-analysis.

The original version of this article unfortunately has a typo error. The name of the author "Kamalan Jeeveratnam" should be presented as "Kamalan Jeevaratnam" as shown above.

Restitution metrics in Brugada syndrome: a systematic review and meta-analysis.

BACKGROUND: Brugada syndrome (BrS) is an ion channelopathy that predisposes affected subjects to ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac death. Restitution analysis has been examined in BrS patients but not all studies have reported significant differences between BrS patients and controls. Therefore, we conducted a systematic review and meta-analysis to investigate the different restitution indices used in BrS. METHODS: PubMed and Embase were searched until April 7, 2019, identifying 20 and 27 studies. RESULTS: A total of ten studies involving 178 BrS (mean age 38 years old, 63% male) and 102 controls (mean age 31 years old, 42% male) were included in this systematic review. Pacing was carried out at the right ventricular outflow tract (RVOT)/right ventricular apex (RPA) (n = 4), RPA (n = 4), or right atrium (RA) (n = 1). Basic cycle lengths of 400 (n = 4), 500 (n = 2), 600 (n = 6) and 750 ms (n = 1) were used. Recording methods include electrograms (n = 4), monophasic action potentials (n = 5), and electrocardiograms (n = 1). Signals were obtained from the RVOT (n = 8), RVA (n = 3), RA (n = 1), or the body surface (n = 1). The maximum restitution slope for endocardial repolarization at the RVOT was 0.87 for BrS patients (n = 5; 95% confidence interval [CI] 0.68-1.07) compared with 0.74 in control subjects (n = 4; 95% CI 0.42-1.06), with a significant mean difference of 0.40 (n = 4; 95% CI 0.11-0.69; P = 0.007). CONCLUSIONS: Steeper endocardial repolarization restitution slopes are found in BrS patients compared with controls at baseline. Restitution analysis can provide important information for risk stratification in BrS.

Temporal Variability in Electrocardiographic Indices in Subjects With Brugada Patterns.

INTRODUCTION: Patients with Brugada electrocardiographic (ECG) patterns have differing levels of arrhythmic risk. We hypothesized that temporal variations in certain ECG markers may provide additional value for risk stratification. The present study evaluated the relationship between temporal variability of ECG markers and arrhythmic outcomes in patients with a Brugada pattern ECG. Comparisons were made between low-risk asymptomatic subjects versus high-risk symptomatic patients with a history of syncope, ventricular tachycardia (VT) or ventricular fibrillation (VF). METHODS: A total of 81 patients presenting with Brugada patterns were recruited. Serial ECGs and electronic health records from January 2004 to April 2019 were analyzed. Temporal variability of QRS interval, J point-Tpeak interval (JTp), Tpeak-Tend interval (Tp-e), and ST elevation (STe) in precordial leads V1-3, in addition to RR-interval from lead II, was assessed using standard deviation and difference between maximum and minimum values over the serial ECGs. RESULTS: Patients presenting with type 1 Brugada ECG pattern initially had significantly higher variability in JTp from lead V2 (SD: 33.5 ± 13.8 vs. 25.2 ± 11.5 ms, P = 0.009; max-min: 98.6 ± 46.2 vs. 78.3 ± 47.6 ms, P = 0.047) and ST elevation in lead V1 (0.117 ± 0.122 vs. 0.053 ± 0.030 mV; P = 0.004). Significantly higher variability in Tp-e interval measured from lead V3 was observed in the VT/VF group compared to the syncope and asymptomatic groups (SD: 20.5 ± 8.5 vs. 16.6 ± 7.3 and 14.7 ± 9.8 ms; P = 0.044; max-min: 70.2 ± 28.9 vs. 56.3 ± 29.0 and 43.5 ± 28.5 ms; P = 0.011). CONCLUSION: Temporal variability in ECG indices may provide additional value for risk stratification in patients with Brugada pattern.

Empirical correlation of triggered activity and spatial and temporal re-entrant substrates with arrhythmogenicity in a murine model for Jervell and Lange-Nielsen syndrome.

KCNE1 encodes the beta-subunit of the slow component of the delayed rectifier K(+) current. The Jervell and Lange-Nielsen syndrome is characterized by sensorineural deafness, prolonged QT intervals, and ventricular arrhythmogenicity. Loss-of-function mutations in KCNE1 are implicated in the JLN2 subtype. We recorded left ventricular epicardial and endocardial monophasic action potentials (MAPs) in intact, Langendorff-perfused mouse hearts. KCNE1 (-/-) but not wild-type (WT) hearts showed not only triggered activity and spontaneous ventricular tachycardia (VT), but also VT provoked by programmed electrical stimulation. The presence or absence of VT was related to the following set of criteria for re-entrant excitation for the first time in KCNE1 (-/-) hearts: Quantification of APD(90), the MAP duration at 90% repolarization, demonstrated alterations in (1) the difference, APD(90), between endocardial and epicardial APD(90) and (2) critical intervals for local re-excitation, given by differences between APD(90) and ventricular effective refractory period, reflecting spatial re-entrant substrate. Temporal re-entrant substrate was reflected in (3) increased APD(90) alternans, through a range of pacing rates, and (4) steeper epicardial and endocardial APD(90) restitution curves determined with a dynamic pacing protocol. (5) Nicorandil (20 microM) rescued spontaneous and provoked arrhythmogenic phenomena in KCNE1 (-/-) hearts. WTs remained nonarrhythmogenic. Nicorandil correspondingly restored parameters representing re-entrant criteria in KCNE1 (-/-) hearts toward values found in untreated WTs. It shifted such values in WT hearts in similar directions. Together, these findings directly implicate triggered electrical activity and spatial and temporal re-entrant mechanisms in the arrhythmogenesis observed in KCNE1 (-/-) hearts.

Arrhythmogenic substrate and its modification by nicorandil in a murine model of long QT type 3 syndrome.

The gain-of-function Scn5a+/DeltaKPQ mutation in the cardiac Na(+) channel causes human long QT type 3 syndrome (LQT3) associated with ventricular arrhythmogenesis. The K(ATP) channel-opener nicorandil (20muM) significantly reduced arrhythmic incidence in Langendorff-perfused Scn5a+/Delta hearts during programmed electrical stimulation; wild-types (WTs) showed a total absence of arrhythmogenicity. These observations precisely correlated with alterations in recently established criteria for re-entrant excitation reflected in: (1) shortened left-ventricular epicardial but not endocardial monophasic action potential durations at 90% repolarization (APD(90)) that (2) restored transmural repolarization gradients, DeltaAPD(90). Scn5a+/Delta hearts showed longer epicardial but not endocardial APD(90)s, giving shorter DeltaAPD(90)s than WT hearts. Nicorandil reduced epicardial APD(90) in both Scn5a+/Delta and WT hearts thereby increasing DeltaAPD(90). (3) Reduced epicardial critical intervals for re-excitation; Scn5a+/Delta hearts showed greater differences between APD(90) and ventricular effective refractory period than WT hearts that were reduced by nicorandil. (4) Reduced APD(90) alternans. Scn5a+/Delta hearts showed greater epicardial and endocardial alternans than WTs, which increased with pacing rate. Nicorandil reduced these in Scn5a+/Delta hearts to levels indistinguishable from untreated WTs. (5) Flattened restitution curves. Scn5a+/Delta hearts showed larger epicardial and endocardial critical diastolic intervals than WT hearts. Nicorandil decreased these in Scn5a+/Delta and WT hearts. The presence or absence of arrhythmogenesis in Scn5a+/Delta and WT hearts thus agreed with previously established criteria for re-entrant excitation, and alterations in these precisely correlated with the corresponding antiarrhythmic effects of nicorandil. Together these findings implicate spatial and temporal re-entrant mechanisms in arrhythmogenesis in LQT3 and their reversal by nicorandil.

Cangrelor versus Ticagrelor in Patients Treated with Primary Percutaneous Coronary Intervention: Impact on Platelet Activity, Myocardial Microvascular Function and Infarct Size: A Randomized Controlled Trial.

BACKGROUND: Oral P2Y12 inhibitors take more than 2 hours to achieve full effect in healthy subjects and this action is further delayed in patients with acute myocardial infarction. Intravenous P2Y12 inhibition might lead to more timely and potent anti-platelet effect in the context of emergency primary angioplasty, improving myocardial recovery. OBJECTIVES: This article compares the efficacy of intravenous cangrelor versus ticagrelor in a ST-elevation myocardial infarction (STEMI) population treated with primary percutaneous coronary intervention (PPCI). MATERIALS AND METHODS: In an open-label, prospective, randomized controlled trial, 100 subjects with STEMI were assigned 1:1 to intravenous cangrelor or oral ticagrelor. The co-primary endpoints were platelet P2Y12 inhibition at infarct vessel balloon inflation time, 4 and 24 hours. Secondary endpoints included indices of coronary microcirculatory function: index of microvascular resistance (IMR), initial infarct size (troponin at 24 hours) and final infarct size at 12 weeks (cardiac magnetic resonance). Secondary endpoints included indices of coronary microcirculatory function (index of microvascular resistance [IMR]), initial infarct size (troponin at 24 hours), final infarct size at 12 weeks (cardiac magnetic resonance), corrected thrombolysis in myocardial infarction (TIMI) frame count, TIMI flow grade, myocardial perfusion grade, and ST-segment resolution (ClinicalTrials.gov NCT02733341). RESULTS: P2Y12 inhibition at first balloon inflation time was significantly greater in cangrelor-treated patients (cangrelor P2Y12 reaction unit [PRU] 145.2 ± 50.6 vs. ticagrelor 248.3 ± 55.1). There was no difference in mean PRU at 4 and 24 to 36 hours post-dosing. IMR, final infarct size, angiographic and electrocardiographic measures of reperfusion were all similar between groups. CONCLUSION: Cangrelor produces more potent P2Y12 inhibition at the time of first coronary balloon inflation time compared with ticagrelor. Despite this enhanced P2Y12 inhibition, coronary microvascular function and final infarct size did not differ between groups.