Rapid vaccine-induced population immunity is a key global strategy to control COVID-19. Vaccination programmes must maximise early impact, particularly with accelerated spread of new variants.1 Most ...vaccine platforms use a two-dose prime-boost approach to generate an immune response against the virus S1 spike protein, the titres of which correlate with functional virus neutralisation and increase with boosting.2,3 To enable larger numbers of people to receive the first dose, delayed administration of the second dose has been advocated and implemented by some.1 The impact of previous SARS-CoV-2 infection on the need for boosting is not known. To test this, we undertook a nested case-control analysis of 51 participants of COVIDsortium,4,5 an ongoing longitudinal observational study of health-care workers (HCWs) in London who underwent weekly PCR and quantitative serology testing from the day of the first UK lockdown on March 23, 2020, and for 16 weeks onwards. 24 of 51 HCWs had a previous laboratory-confirmed mild or asymptomatic SARS-CoV-2 infection, as confirmed by positive detection of antibodies against the SARS-CoV-2 nucleocapsid (Elecsys Anti-SARS-CoV-2 N ECLIA, Roche Diagnostics, Burgess Hill, UK) or the receptor binding domain of the SARS-CoV-2 S1 subunit of the spike protein (anti-S; Elecsys anti-SARS-CoV-2 spike ECLIA, Roche Diagnostics), whereas 27 HCWs remained seronegative.
The exponential growth in coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) across the UK has been successfully reversed by social distancing ...and lockdown.1 RNA testing for prevalent infection is a key part of the exit strategy, but the role of testing for asymptomatic infection remains unclear.2 Understanding the determinants of asymptomatic or pauci-symptomatic infection will provide new opportunities for personalised risk stratification and reveal much-needed correlates of protective immunity, whether induced by vaccination or natural exposure. To address this, we set up COVIDsortium (NCT04318314), a bioresource focusing on asymptomatic health-care workers (HCWs—doctors, nurses, allied health professionals, administrators, and others) at Barts Health NHS Trust, London, UK, to collect data through 16 weekly assessments (unless ill, self-isolating, on holiday, or redeployed) with a health questionnaire, nasal swab, and blood samples and two concluding assessments at 6 month and 12 months. HCWs have been particularly hard hit by the COVID-19 pandemic, with high reported rates of infection from Italian data,3 raising concerns about the effectiveness of personal protective equipment and of nosocomial transmission.4 Public fear of hospitals is also currently high, and many serious and treatable diseases are presenting late with adverse outcomes.5 Testing of HCWs has so far been restricted to symptomatic individuals, and no studies have reported serial testing in high-exposure asymptomatic volunteers.
Abstract
Background
Troponin elevation is common in hospitalized COVID-19 patients, but underlying aetiologies are ill-defined. We used multi-parametric cardiovascular magnetic resonance (CMR) to ...assess myocardial injury in recovered COVID-19 patients.
Methods and results
One hundred and forty-eight patients (64 ± 12 years, 70% male) with severe COVID-19 infection all requiring hospital admission, 48 (32%) requiring ventilatory support and troponin elevation discharged from six hospitals underwent convalescent CMR (including adenosine stress perfusion if indicated) at median 68 days. Left ventricular (LV) function was normal in 89% (ejection fraction 67% ± 11%). Late gadolinium enhancement and/or ischaemia was found in 54% (80/148). This comprised myocarditis-like scar in 26% (39/148), infarction and/or ischaemia in 22% (32/148) and dual pathology in 6% (9/148). Myocarditis-like injury was limited to three or less myocardial segments in 88% (35/40) of cases with no associated LV dysfunction; of these, 30% had active myocarditis. Myocardial infarction was found in 19% (28/148) and inducible ischaemia in 26% (20/76) of those undergoing stress perfusion (including 7 with both infarction and ischaemia). Of patients with ischaemic injury pattern, 66% (27/41) had no past history of coronary disease. There was no evidence of diffuse fibrosis or oedema in the remote myocardium (T1: COVID-19 patients 1033 ± 41 ms vs. matched controls 1028 ± 35 ms; T2: COVID-19 46 ± 3 ms vs. matched controls 47 ± 3 ms).
Conclusions
During convalescence after severe COVID-19 infection with troponin elevation, myocarditis-like injury can be encountered, with limited extent and minimal functional consequence. In a proportion of patients, there is evidence of possible ongoing localized inflammation. A quarter of patients had ischaemic heart disease, of which two-thirds had no previous history. Whether these observed findings represent pre-existing clinically silent disease or de novo COVID-19-related changes remain undetermined. Diffuse oedema or fibrosis was not detected.
Graphical Abstract
Abstract
Aims
To investigate myocardial fibrosis (MF) in a large series of severe aortic stenosis (AS) patients using invasive biopsy and non-invasive imaging.
Methods and results
One hundred ...thirty-three patients with severe, symptomatic AS accepted for surgical aortic valve replacement underwent cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) and extracellular volume fraction (ECV) quantification. Intra-operative left ventricular (LV) biopsies were performed by needle or scalpel, yielding tissue with (n = 53) and without endocardium (n = 80), and compared with 10 controls. Myocardial fibrosis occurred in three patterns: (i) thickened endocardium with a fibrotic layer; (ii) microscopic scars, with a subendomyocardial predominance; and (iii) diffuse interstitial fibrosis. Collagen volume fraction (CVF) was elevated (P < 0.001) compared with controls, and higher (P < 0.001) in endocardium-containing samples with a decreasing CVF gradient from the subendocardium (P = 0.001). Late gadolinium enhancement correlated with CVF (P < 0.001) but not ECV. Both LGE and ECV correlated independently (P < 0.001) with N-terminal pro-brain natriuretic peptide and high-sensitivity-troponin T. High ECV was also associated with worse LV remodelling, left ventricular ejection fraction and functional capacity. Combining high ECV and LGE better identified patients with more adverse LV remodelling, blood biomarkers and histological parameters, and worse functional capacity than each parameter alone.
Conclusion
Myocardial fibrosis in severe AS is complex, but three main patterns exist: endocardial fibrosis, microscars (mainly in the subendomyocardium), and diffuse interstitial fibrosis. Neither histological CVF nor the CMR parameters ECV and LGE capture fibrosis in its totality. A combined, multi-parametric approach with ECV and LGE allows best stratification of AS patients according to the response of the myocardial collagen matrix.
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.
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.
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.
Wild-type transthyretin amyloid (wtATTR) affects the heart, causing a restrictive cardiomyopathy-deposits can be found in up to 25% of individuals >85 years of age at autopsy (1,2). ...recently, ...diagnosis required endomyocardial biopsy. ...the amyloid burden was skewed: rather than a pyramidal distribution with DPD grade 1>2>3, DPD grade 2 was dominant. The importance of ongoing studies is high. 1 J.D. Gillmore, M.S. Maurer, R.H. Falk, Nonbiopsy diagnosis of cardiac transthyretin amyloidosis, Circulation, Vol. 133, 2016, 2404-2412 2 M. Tanskanen, T. Peuralinna, T. Polvikoski, Ann Med, Vol. 40, 2008, 232-239 3 A. Castaño, D.L. Narotsky, N. Hamid, Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement, Eur Heart J, Vol. 38, 2017, 2879-2887 4 T.A. Treibel, M. Fontana, J.A. Gilbertson, Occult transthyretin cardiac amyloid in severe calcific aortic stenosis: prevalence and prognosis in patients undergoing surgical aortic valve replacement, Circ Cardiovasc Imaging, Vol. 9, 2016, e005066 5 E. González-López, M. Gallego-Delgado, G. Guzzo-Merello, Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction, Eur Heart J, Vol. 36, 2015, 2585-2594
BACKGROUND—The prognosis and treatment of the 2 main types of cardiac amyloidosis, immunoglobulin light chain (AL) and transthyretin (ATTR) amyloidosis, are substantially influenced by cardiac ...involvement. Cardiovascular magnetic resonance with late gadolinium enhancement (LGE) is a reference standard for the diagnosis of cardiac amyloidosis, but its potential for stratifying risk is unknown.
METHODS AND RESULTS—Two hundred fifty prospectively recruited subjects, 122 patients with ATTR amyloid, 9 asymptomatic mutation carriers, and 119 patients with AL amyloidosis, underwent LGE cardiovascular magnetic resonance. Subjects were followed up for a mean of 24±13 months. LGE was performed with phase-sensitive inversion recovery (PSIR) and without (magnitude only). These were compared with extracellular volume measured with T1 mapping. PSIR was superior to magnitude-only inversion recovery LGE because PSIR always nulled the tissue (blood or myocardium) with the longest T1 (least gadolinium). LGE was classified into 3 patternsnone, subendocardial, and transmural, which were associated with increasing amyloid burden as defined by extracellular volume (P<0.0001), with transitions from none to subendocardial LGE at an extracellular volume of 0.40 to 0.43 (AL) and 0.39 to 0.40 (ATTR) and to transmural at 0.48 to 0.55 (AL) and 0.47 to 0.59 (ATTR). Sixty-seven patients (27%) died. Transmural LGE predicted death (hazard ratio, 5.4; 95% confidence interval, 2.1–13.7; P<0.0001) and remained independent after adjustment for N-terminal pro-brain natriuretic peptide, ejection fraction, stroke volume index, E/E′, and left ventricular mass index (hazard ratio, 4.1; 95% confidence interval, 1.3–13.1; P<0.05).
CONCLUSIONS—There is a continuum of cardiac involvement in systemic AL and ATTR amyloidosis. Transmural LGE is determined reliably by PSIR and represents advanced cardiac amyloidosis. The PSIR technique provides incremental information on outcome even after adjustment for known prognostic factors.
This study evaluated the prognostic potential of native myocardial T1 in cardiac transthyretin amyloidosis (ATTR) and compared native T1 with extracellular volume (ECV) in terms of diagnostic ...accuracy and prognosis.
ATTR is an increasingly recognized cause of heart failure that has an overlapping clinical phenotype with hypertrophic cardiomyopathy (HCM). Native T1 mapping by cardiac magnetic resonance (CMR) is useful for diagnosis in cardiac amyloidosis but its prognostic potential has never been assessed.
A total of 134 patients with wild-type ATTR (ATTRwt) (122 men; age 76 ± 7 years), 81 patients with hereditary-type ATTR (ATTRm) (60 men; age 69 ± 11 years), 44 patients with HCM (32 men; age 51 ± 13 years), and 12 asymptomatic mutation carriers (4 men; age 47 ± 10 years) were studied. All subjects underwent CMR with T1 mapping and ECV measurement. ATTR patients also underwent 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy.
Native T1 and ECV were elevated in ATTR compared with HCM (p < 0.001) and were both associated with a high diagnostic accuracy (area under the curve AUC: 0.87; 95% confidence interval CI: 0.82 to 0.91) for T1 and an AUC of 0.91 (95% CI: 0.87 to 0.94) for ECV. No significant difference in native T1 and ECV was found between ATTRwt and ATTRm, and ECV correlated well with 99mTc-DPD scintigraphy. During follow-up of a mean of 32 ± 17 months, 55 ATTRwt and 40 ATTRm patients died. Native T1 and ECV predicted death (T1: hazard ratio HR: 1.225 for each 59-ms increase; 95% CI: 1.010 to 1.486; p < 0.05; ECV: HR: 1.155 for each 3% increase; 95% CI: 1.097 to 1.216; p < 0.001), but only ECV remained independently predictive after adjustment for age, N-terminal pro−B-type natriuretic peptide, left ventricular ejection fraction, E/E′, left ventricular mass index, DPD grade, and late gadolinium enhancement.
Native T1 mapping and ECV are good diagnostic techniques for cardiac ATTR that are associated with prognosis. Both parameters correlated with mortality, but only ECV remained independently predictive of prognosis, suggesting that it is a more robust marker in cardiac ATTR.
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Abstract
Aims
Cardiac amyloidosis is common in elderly patients with aortic stenosis (AS) referred for transcatheter aortic valve implantation (TAVI). We hypothesized that patients with dual aortic ...stenosis and cardiac amyloid pathology (AS-amyloid) would have different baseline characteristics, periprocedural and mortality outcomes.
Methods and results
Patients aged ≥75 with severe AS referred for TAVI at two sites underwent blinded bone scintigraphy prior to intervention (Perugini Grade 0 negative, 1–3 increasingly positive). Baseline assessment included echocardiography, electrocardiogram (ECG), blood tests, 6-min walk test, and health questionnaire, with periprocedural complications and mortality follow-up. Two hundred patients were recruited (aged 85 ± 5 years, 50% male). AS-amyloid was found in 26 (13%): 8 Grade 1, 18 Grade 2. AS-amyloid patients were older (88 ± 5 vs. 85 ± 5 years, P = 0.001), with reduced quality of life (EQ-5D-5L 50 vs. 65, P = 0.04). Left ventricular wall thickness was higher (14 mm vs. 13 mm, P = 0.02), ECG voltages lower (Sokolow–Lyon 1.9 ± 0.7 vs. 2.5 ± 0.9 mV, P = 0.03) with lower voltage/mass ratio (0.017 vs. 0.025 mV/g/m2, P = 0.03). High-sensitivity troponin T and N-terminal pro-brain natriuretic peptide were higher (41 vs. 21 ng/L, P < 0.001; 3702 vs. 1254 ng/L, P = 0.001). Gender, comorbidities, 6-min walk distance, AS severity, prevalence of disproportionate hypertrophy, and post-TAVI complication rates (38% vs. 35%, P = 0.82) were the same. At a median follow-up of 19 (10–27) months, there was no mortality difference (P = 0.71). Transcatheter aortic valve implantation significantly improved outcome in the overall population (P < 0.001) and in those with AS-amyloid (P = 0.03).
Conclusions
AS-amyloid is common and differs from lone AS. Transcatheter aortic valve implantation significantly improved outcome in AS-amyloid, while periprocedural complications and mortality were similar to lone AS, suggesting that TAVI should not be denied to patients with AS-amyloid.
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