During Primary Percutaneous Coronary Intervention (PPCI) post ST-Segment Myocardial Infarction (STEMI), distal embolisation of thrombus may lead to failure to re-establish normal flow in the infarct-related artery. Manual thrombus aspiration has been shown to improve coronary perfusion as assessed by time to ST-segment resolution and myocardial blush grade. Evidence supporting the benefit of thrombus aspiration on clinical outcomes, however, is limited and inconsistent. We aimed to assess the impact of manual thrombectomy on mortality in patients presenting with STEMI across all PPCI centres in London over a 5 year period from 2007 until 2012.
Methods
This was an observational cohort study of 9935 consecutive patients with STEMI treated with PPCI between 2007 and 2012 at eight tertiary cardiac centres across London, UK. Patient9s details were recorded at the time of the procedure into the British Cardiac Intervention Society (BCIS) database. Outcome was assessed by all-cause mortality. Anonymous datasets from the eight centres were merged for analysis. The primary end-point was all-cause mortality at a median follow-up of 2.0 years (IQR range 1.1–3.1 years).
Results
Of the 9935 consecutive STEMI patients presenting for PPCI, 2859 had mechanical thrombectomy. Patients who had manual thrombectomy were significantly younger (average age 60.6 vs 62.9) and were less likely to have had a previous myocardial infarction (11.9% of thrombectomy patients vs 14.7% of non-thrombectomy patients). Patients receiving manual thromectomy were found to be significantly more likely to have had PPCI via a radial approach (33.1% in thrombectomy patients vs 19.9% in non-thromectomy patients). Procedural success (defined as TIMI 3 flow at the end of procedure) was found to be significantly more likely in patients receiving manual thrombectomy (89.5% vs 86.7%) (table 1). Patients with thrombectomy use had similar unadjusted all-cause mortality rates to those without thrombectomy use (12.7% vs 16.5%, p=NS) during the 5-year follow-up period (figure 1). After multivariable adjustment thrombectomy use was associated with significantly decreased mortality rates (HR: 0.82, 95% CI 0.68 to 0.9, p=0.04).
Conclusion
Mechanical thrombectomy use appears to be associated with improved outcome, in the form of decreased mortality, in this large observational trial.
Introduction: The diagnostic performance of EKG in ruling out myocardial abnormalities following COVID-19 is unclear. Aim: To assess the ability of EKG to exclude cardiac abnormalities on cardiac magnetic resonance imaging (CMR) in post-hospitalised COVID-19 patients. Methods: Post-hospitalized patients (n=212) & comorbidities matched controls (n=38) underwent CMR and 12-lead EKG. EKG assessments included depolarization & repolarization abnormalities [ QTc , corrected QT dispersion ( QTc disp ), JT ( JTc ) & T peak-end ( cTPe ) intervals]. CMR abnormalities were defined as reduced left ventricular ejection fraction (LVEF), high T1 & T2 Z scores and high extracellular volume and pathological late gadolinium enhancement. Results: At 5.6 months post-discharge, patients had a higher burden of EKG abnormalities vs controls (72.2% vs 42.1%, p=0.001 ) (Figure A) . CMR abnormalities were comparable despite patients having lower LVEF. Abnormal EKG findings and prolonged repolarization were more common in patients with CMR abnormalities vs patients with normal CMR and controls ( Figure A & B ). Area-under-the-receiver-operating curve (AUROC) of routine EKG abnormalities to discriminate abnormal CMR was 0.56 (95% CI 0.47-0.65), p=0.185. Inclusion of JTc & QTc disp improved the AUROC to 0.64 (95% CI 0.55-0.74), p=0.002. Inclusion of JTc ≥340ms & QTc disp ≥40ms improved the sensitivity from 81.6% to 99.9% with higher negative predictive value (84.7% to 99.9%) ( Figure A ). Conclusions: Post-hospitalized COVID-19 patients have more EKG abnormalities than comorbidities-matched controls. A normal EKG with normal repolarization is effective in ruling out significant CMR abnormalities.
The international healthcare response to COVID-19 has been driven by epidemiological data related to case numbers and case fatality rate. Second order effects have been less well studied. This study aimed to characterise the changes in emergency activity of a high-volume cardiac catheterisation centre and to cautiously model any excess indirect morbidity and mortality. Retrospective cohort study of patients admitted with acute coronary syndrome fulfilling criteria for the heart attack centre (HAC) pathway at St. Bartholomew's hospital, UK. Electronic data were collected for the study period March 16th – May 16th 2020 inclusive and stored on a dedicated research server. Standard governance procedures were observed in line with the British Cardiovascular Intervention Society audit. There was a 28% fall in the number of primary percutaneous coronary interventions (PCIs) for ST elevation myocardial infarction (STEMI) during the study period (111 vs. 154) and 36% fewer activations of the HAC pathway (312 vs. 485), compared to the same time period averaged across three preceding years. In the context of 'missing STEMIs', the excess harm attributable to COVID-19 could result in an absolute increase of 1.3% in mortality, 1.9% in nonfatal MI and 4.5% in recurrent ischemia. The emergency activity of a high-volume PCI centre was significantly reduced for STEMI during the peak of the first wave of COVID-19. Our data can be used as an exemplar to help future modelling within cardiovascular workstreams to refine aggregate estimates of the impact of COVID-19 and inform targeted policy action.
Abstract Aims Myocardial scar detected by cardiovascular magnetic resonance has been associated with sudden cardiac death in dilated cardiomyopathy (DCM). Certain genetic causes of DCM may cause a malignant arrhythmogenic phenotype. The concepts of arrhythmogenic left ventricular (LV) cardiomyopathy (ALVC) and arrhythmogenic DCM are currently ill-defined. We hypothesized that a distinctive imaging phenotype defines ALVC. Methods and results Eighty-nine patients with DCM-associated mutations [desmoplakin (DSP) n = 25, filamin C (FLNC) n = 7, titin n = 30, lamin A/C n = 12, bcl2-associated athanogene 3 n = 3, RNA binding motif protein 20 n = 3, cardiac sodium channel NAv1.5 n = 2, and sarcomeric genes n = 7] were comprehensively phenotyped. Clustering analysis resulted in two groups: ‘DSP/FLNC genotypes’ and ‘non-DSP/FLNC’. There were no significant differences in age, sex, symptoms, baseline electrocardiography, arrhythmia burden, or ventricular volumes between the two groups. Subepicardial LV late gadolinium enhancement with ring-like pattern (at least three contiguous segments in the same short-axis slice) was observed in 78.1% of DSP/FLNC genotypes but was absent in the other DCM genotypes (P < 0.001). Left ventricular ejection fraction (LVEF) and global longitudinal strain were lower in other DCM genotypes (P = 0.053 and P = 0.015, respectively), but LV regional wall motion abnormalities were more common in DSP/FLNC genotypes (P < 0.001). DSP/FLNC patients with non-sustained ventricular tachycardia (NSVT) had more LV scar (P = 0.010), whereas other DCM genotypes patients with NSVT had lower LVEF (P = 0.001) than patients without NSVT. Conclusion DSP/FLNC genotypes cause more regionality in LV impairment. The most defining characteristic is a subepicardial ring-like scar pattern in DSP/FLNC, which should be considered in future diagnostic criteria for ALVC.
Abstract Introduction Arrhythmogenic Cardiomyopathy (AC) is typically caused by mutations in the desmosomal genes, however non-desmosomal genes have been increasingly implicated. Desmin gene (DES) mutations have been previously reported in AC, but in many cases there are insufficient data to support their pathogenicity. Purpose We assessed our AC cohort for DES gene mutations and describe the clinical phenotype associated with a recurring variant present in 3 unrelated families. Methods Genetic testing was performed using next-generation sequencing for 41 genes in a total of 138 AC probands with a definite diagnosis of AC based on the revised 2010 Task Force diagnostic criteria. All candidate variants were confirmed using Sanger sequencing. Clinical and genetic cascade screening were expanded to the first-degree relatives of the probands. Retained tissue from deceased individuals was used for genetic testing. All living mutation carriers underwent clinical assessment including physical examination, 12-lead ECG, signal-averaged ECG, echocardiography, cardiac magnetic resonance imaging (MRI) and 24h Holter-monitoring. Results Two DES gene variants, p.Ser298Leu (n=1) and p.Leu115Ile (n=3), were identified in 4 out of the 138 probands (3%). The former coexisted with a pathogenic DSP gene mutation and has not been further evaluated. The latter is a novel variant, absent in control databases (gnomAD) and was the only variant present in 3 unrelated families (see figure). One carrier required heart transplant (A-II-1), two died suddenly (A-III-1, B-II-1) and one died of non-cardiac causes (B-I-2). Detailed clinical information was present in 8 mutation carriers (2 male, age 45±19 years). Seven (88%) had a definite diagnosis and one had a borderline diagnosis of AC. All cases (100%) had right ventricular (RV) wall motion abnormalities, 6 (75%) had a dilated RV, 6 (75%) a dilated LV and 6 (75%) had LV dysfunction (mild in 5 and severe in 1). LV late gadolinium enhancement (LGE) was present in all 6 carriers that had a cardiac MRI with a circumferential sub-epicardial distribution (see figure, case A-III-2). Non-sustained ventricular tachycardia (VT) was present in 7 (88%) and sustained VT in 2 cases (25%). The ventricular ectopic burden per 24h ranged from 426 to 10583 with a median value of 820. Figure 1 Conclusion Variants of the DES gene are rare causes of AC. The novel p.Leu115Ile variant seems to be prevalent in a large UK-based cohort and it causes a biventricular form of AC, with a characteristic scar pattern on MRI and severe outcomes. Acknowledgement/Funding Alexandros Protonotarios is supported by a BHF Clinical Research Training Fellowship no. FS/18/82/34024
Diagnostic genetic testing is an integral part of patient management in hypertrophic cardiomyopathy (HCM). Over time, the number of genes included in diagnostic genetic panels increased. The aim of the systematic review was to examine the impact of panel size on diagnostic yield.
Methods
All cohort studies reporting the results of genetic testing in HCM patients were included, irrespective of setting. PubMed/Medline was searched from May 2000 (advent of next generation sequencing technology) to May 2018 using the following terms: (Hypertrophic Cardiomyopathy OR Hypertrophic Obstructive cardiomyopathy OR HCM OR HOCM) AND (Genotype OR Genetic Testing OR HCM panel OR pathogenic OR variant of unknown significance OR VUS OR Next Generation Sequencing OR Gene* Test* OR Genotyp*). The systematic review was carried out in accordance to the Preferred Reporting Items for Systematic reviews and Meta-Analyses amendment (PRISMA).
Results
A total of 4837 articles fulfilled the search criteria in PubMed and 55 observational studies were included in the systematic review. Most study cohorts were derived from European countries (47%) and involved a single centre (73%). Prospective data collection was employed in 32 (58%) studies. The median cohort size was 124 patients (IQR 70–299). At least five studies included individuals ≤16 years of age (the minimum age was not reported in 47 (85%) studies). The studies tested 2 to 15 sarcomeric protein genes (median 8 genes; IQR: 5–10), including MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, ACTC1, TPM1, TNNC1, MYH6, CSRP3, DES, TCAP, PDLIM3, PLN. All studies tested for mutations in MYBPC3 and MYH7 and most studies additionally included at least one of the following genes: TNNT2, TNNI3, MYL2, MYL3, ACTC1 and TPM1. The majority of positive mutations identified were in MYBPC3 (20%) and MYH7 (12%) (see figure 1). For all other sarcomeric genes, yield was <3%. Percentage yield varied greatly between studies with a range of 19–90% (mean 44%) and showed no discernible relationship with panel size (see figure 2).
Conclusion
Over time, the number of genes included on HCM diagnostic genetic panels has increased but this has not translated to a significant improvement in diagnostic yield. Larger panels may introduce more complexity and uncertainty in the clinical setting and some of the high diagnostic yields may be explained by lax variant interpretation methods.
Hypertrophic cardiomyopathy (HCM) is most commonly transmitted as an autosomal dominant trait, caused by mutations in genes encoding cardiac sarcomere proteins. Other inheritable causes of the disease include mutations in genes coding for proteins important in calcium handling or that form part of the cytoskeleton. At present, the primary clinical role of genetic testing in HCM is to facilitate familial screening to allow the identification of individuals at risk of developing the disease. It is also used to diagnose genocopies, such as lysosomal and glycogen storage disease which have different treatment strategies, rates of disease progression and prognosis. The role of genetic testing in predicting prognosis is limited at present, but emerging data suggest that knowledge of the genetic basis of disease will assume an important role in disease stratification and offer potential targets for disease-modifying therapy in the near future.
Abstract Background Predictive genetic screening of the first degree relatives of patients with hypertrophic cardiomyopathy (HCM) caused by sarcomere protein (SP) gene mutations is current standard of care, but there are few data on long-term outcomes in mutation carriers without HCM. Purpose To establish the role of sex and genotype in HCM penetrance as well as the rate of major adverse clinical events in SP mutation carriers and following the diagnosis of HCM. Methods Retrospective analysis of consecutive adult and paediatric SP mutation carriers identified during family screening and who did not fulfill diagnostic criteria for HCM at first evaluation. Results 321 individuals from 170 families [median age first evaluation 15.2 years (IQR 7.3–32.6); 153 (47.7%) males] were evaluated. Causal SP genes were: MYBPC3 (n=133 (41.4%)), MYH7 (n=77 (24.0%)), TNNI3 (n=51 (15.9%)), TNNT2 (n=40 (12.5%)), TPM1 (n=9 (2.8%)), MYL2 (n=6 (1.9%)), and ACTC1 (n=1 (0.3%)); 4 (1.3%) carried multiple mutations. After a median follow up of 7.4 years (IQR 2.5–12.7), 89 (27.7%) patients developed HCM. Disease penetrance at the age of 50 years was 47% (95% CI 38%-56%). One hundred and fifty three (47.7%) individuals underwent cardiac magnetic resonance (CMR) imaging; among those diagnosed with HCM, 22/89 (24.7%) fulfilled criteria on CMR but not echocardiography. In a multivariable model adjusted for genotype, follow up duration and evaluation with CMR, independent predictors of HCM development were male sex (HR 3.11; CI 1.82–5.32) and abnormal ECG (HR 7.87; CI 4.43–13.97). Patients with MYH7 and multiple mutations were more likely to develop HCM than those with MYBPC3 mutations (HR 2.03; CI 1.04–3.96 and HR 10.13; CI 1.40–72.92, respectively). Disease penetrance was lowest in carriers of TNNI3 mutations (HR 0.13; CI 0.03–0.48). There were no major adverse events in individuals without HCM. Following the diagnosis of HCM, the combined rate of all-cause death, appropriate defibrillator shock or resuscitated cardiac arrest was 1.1%/year [median follow up 4.0 years (IQR 2.1–8.9)]. Conclusions Approximately 50% of SP mutation carriers develop HCM by the age of 50 and become prone to disease complications during long-term follow-up. Sex, MYH7 mutations and the presence of an abnormal ECG are associated with a higher risk of disease development. CMR should be employed systematically in long-term screening. HCM penetrance by sex Funding Acknowledgement Type of funding source: None
Abstract Introduction Desmoplakin (DSP) gene mutations are reported to cause arrhythmogenic right ventricular cardiomyopathy (ARVC), but recent evidence suggests that they manifest as a much broader range of phenotypes. Purpose To describe the phenotypic characteristics of DSP mutation carriers in a consecutive cohort of patients with heart muscle disease. Methods A retrospective analysis of consecutive patients with heart muscle disease and their relatives that underwent diagnostic or research genetic testing. Only DSP variants classified as pathogenic by the American College of Medical Genetics and Genomics criteria were considered. Dilated cardiomyopathy (DCM), hypokinetic non-dilated cardiomyopathy (HNDC) and ARVC were diagnosed in accordance with current criteria. Results 109 mutation carriers were identified: 34 (31%) had DCM and 23 (21%) HNDC. ARVC diagnosis was borderline and definite in 39 (36%) and 39 (36%) individuals, respectively. Sixteen (15%) presented with clinically suspected myocarditis. 23 patients met both definite AC and DCM criteria and 13 patients met definite AC and HNDC criteria. In 87 patients with cardiac magnetic resonance imaging, a spectrum of disease was observed (Table) including an intermediate phenotype characterised by subepicardial LV fibrosis in the absence of ventricular dilatation or dysfunction. Ventricular dysfunction was manifest as left dominant disease (n=22, 48%) and biventricular disease (n=24, 52%); none had right dominant disease. Conclusions DSP mutations are associated with left and biventricular phenotypes and can present as myocarditis. Current ARVC and DCM diagnostic criteria inadequately describe the clinical subtypes of DSP related disease. A novel approach to disease classification is proposed. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation
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