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
The aim of this study was to characterize left atrial (LA) pathology in explanted hearts with transthyretin amyloid cardiomyopathy (ATTR-CM); LA mechanics using echocardiographic speckle-tracking in ...a large cohort of patients with ATTR-CM; and to study the association with mortality.
The clinical significance of LA involvement in ATTR-CM is of great clinical interest.
Congo red staining and immunohistochemistry was performed to assess the presence, type, and extent of amyloid and associated changes in 5 explanted ATTR-CM atria. Echo speckle tracking was used to assess LA reservoir, conduit, contractile function, and stiffness in 906 patients with ATTR-CM (551 wild-type (wt)-ATTR-CM; 93 T60A-ATTR-CM; 241 V122I-ATTR-CM; 21 other).
There was extensive ATTR amyloid infiltration in the 5 atria, with loss of normal architecture, vessels remodeling, capillary disruption, and subendocardial fibrosis. Echo speckle tracking in 906 patients with ATTR-CM demonstrated increased atrial stiffness (median 25th-75th quartile 1.83 1.15-2.92) that remained independently associated with prognosis after adjusting for known predictors (lnLA stiff: HR: 1.23; 95% CI: 1.03-1.49; P = 0.029). There was substantial impairment of the 3 phasic functional atrial components (reservoir 8.86% 5.94%-12.97%; conduit 6.5% 4.53%-9.28%; contraction function 4.0% 2.29%-6.56%). Atrial contraction was absent in 22.1% of patients whose electrocardiograms showed sinus rhythm (SR) “atrial electromechanical dissociation” (AEMD). AEMD was associated with poorer prognosis compared with patients with SR and effective mechanical contraction (P = 0.0018). AEMD conferred a similar prognosis to patients in atrial fibrillation.
The phenotype of ATTR-CM includes significant infiltration of the atrial walls, with progressive loss of atrial function and increased stiffness, which is a strong independent predictor of mortality. AEMD emerged as a distinctive phenotype identifying patients in SR with poor prognosis.
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Systemic amyloidosis is a rare, heterogenous group of diseases characterized by extracellular infiltration and deposition of amyloid fibrils. Cardiac amyloidosis (CA) occurs when these fibrils ...deposit within the myocardium. Untreated, this inevitably leads to progressive heart failure and fatality. Historically, treatment has remained supportive, however, there are now targeted disease-modifying therapeutics available to patients with CA. Advances in echocardiography, cardiac magnetic resonance (CMR) and repurposed bone scintigraphy have led to a surge in diagnoses of CA and diagnosis at an earlier stage of the disease natural history. CMR has inherent advantages in tissue characterization which has allowed us to better understand the pathological disease process behind CA. Combined with specialist assessment and repurposed bone scintigraphy, diagnosis of CA can be made without the need for invasive histology in a significant proportion of patients. With existing targeted therapeutics, and novel agents being developed, understanding these imaging modalities is crucial to achieving early diagnosis for patients with CA. This will allow for early treatment intervention, accurate monitoring of disease course over time, and thereby improve the length and quality of life of patients with a disease that historically had an extremely poor prognosis. In this review, we discuss key radiological features of CA, focusing on the two most common types; immunoglobulin light chain (AL) and transthyretin (ATTR) CA. We highlight recent advances in imaging techniques particularly in respect of their clinical application and utility in diagnosis of CA as well as for tracking disease change over time.
Background Ongoing exercise intolerance of unclear cause following COVID-19 infection is well recognized but poorly understood. We investigated exercise capacity in patients previously hospitalized ...with COVID-19 with and without self-reported exercise intolerance using magnetic resonance-augmented cardiopulmonary exercise testing. Methods and Results Sixty subjects were enrolled in this single-center prospective observational case-control study, split into 3 equally sized groups: 2 groups of age-, sex-, and comorbidity-matched previously hospitalized patients following COVID-19 without clearly identifiable postviral complications and with either self-reported reduced (COVID
) or fully recovered (COVID
) exercise capacity; a group of age- and sex-matched healthy controls. The COVID
group had the lowest peak workload (79W Interquartile range (IQR), 65-100 versus controls 104W IQR, 86-148;
=0.01) and shortest exercise duration (13.3±2.8 minutes versus controls 16.6±3.5 minutes;
=0.008), with no differences in these parameters between COVID
patients and controls. The COVID
group had: (1) the lowest peak indexed oxygen uptake (14.9 mL/minper kg IQR, 13.1-16.2) versus controls (22.3 mL/min per kg IQR, 16.9-27.6;
=0.003) and COVID
patients (19.1 mL/min per kg IQR, 15.4-23.7;
=0.04); (2) the lowest peak indexed cardiac output (4.7±1.2 L/min per m
) versus controls (6.0±1.2 L/min per m
;
=0.004) and COVID
patients (5.7±1.5 L/min per m
;
=0.02), associated with lower indexed stroke volume (SVi:COVID
39±10 mL/min per m
versus COVID
43±7 mL/min per m
versus controls 48±10 mL/min per m
;
=0.02). There were no differences in peak tissue oxygen extraction or biventricular ejection fractions between groups. There were no associations between COVID-19 illness severity and peak magnetic resonance-augmented cardiopulmonary exercise testing metrics. Peak indexed oxygen uptake, indexed cardiac output, and indexed stroke volume all correlated with duration from discharge to magnetic resonance-augmented cardiopulmonary exercise testing (
<0.05). Conclusions Magnetic resonance-augmented cardiopulmonary exercise testing suggests failure to augment stroke volume as a potential mechanism of exercise intolerance in previously hospitalized patients with COVID-19. This is unrelated to disease severity and, reassuringly, improves with time from acute illness.
The large number of available MRI sequences means patients cannot realistically undergo them all, so the range of sequences to be acquired during a scan are protocolled based on clinical details. ...Adapting this to unexpected findings identified early on in the scan requires experience and vigilance. We investigated whether deep learning of the images acquired in the first few minutes of a scan could provide an automated early alert of abnormal features. Anatomy sequences from 375 CMR scans were used as a training set. From these, we annotated 1500 individual slices and used these to train a convolutional neural network to perform automatic segmentation of the cardiac chambers, great vessels and any pleural effusions. 200 scans were used as a testing set. The system then assembled a 3D model of the thorax from which it made clinical measurements to identify important abnormalities. The system was successful in segmenting the anatomy slices (Dice 0.910) and identified multiple features which may guide further image acquisition. Diagnostic accuracy was 90.5% and 85.5% for left and right ventricular dilatation, 85% for left ventricular hypertrophy and 94.4% for ascending aorta dilatation. The area under ROC curve for diagnosing pleural effusions was 0.91. We present proof-of-concept that a neural network can segment and derive accurate clinical measurements from a 3D model of the thorax made from transaxial anatomy images acquired in the first few minutes of a scan. This early information could lead to dynamic adaptive scanning protocols, and by focusing scanner time appropriately and prioritizing cases for supervision and early reporting, improve patient experience and efficiency.
Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive and ultimately fatal cardiomyopathy. Biomarkers reflecting multiorgan dysfunction are of increasing importance in patients with heart ...failure; however, their significance in ATTR-CA remains largely unknown. The aims of this study were to characterize the multifaceted nature of ATTR-CA using blood biomarkers and assess the association between blood biomarkers and prognosis.
This is a retrospective cohort study of 2566 consecutive patients diagnosed with ATTR-CA between 2007 and 2023. Anemia (39%), high urea (52%), hyperbilirubinemia (18%), increased alkaline phosphatase (16%), increased CRP (C-reactive protein; 27%), and increased troponin (98.2%) were common findings in the overall population, whereas hyponatremia (6%) and hypoalbuminemia (2%) were less common. These abnormalities were most common in patients with p.(V142I) hereditary ATTR-CA, and became more prevalent as the severity of cardiac disease increased. Multivariable Cox regression analysis demonstrated that anemia (hazard ratio HR, 1.19 95% CI, 1.04-1.37;
=0.01), high urea (HR, 1.23 95% CI, 1.04-1.45;
=0.01), hyperbilirubinemia (HR, 1.32 95% CI, 1.13-1.57;
=0.001), increased alkaline phosphatase (HR, 1.20 95% CI, 1.01-1.42;
=0.04), hyponatremia (HR, 1.65 95% CI, 1.28-2.11;
<0.001), and troponin-T >56 ng/L (HR, 1.72 95% CI, 1.46-2.03;
<0.001) were all independently associated with mortality in the overall population. The association between biomarkers and mortality varied across the spectrum of genotypes and left ventricular ejection fraction, with anemia remining independently associated with mortality in p.(V142I) hereditary ATTR-CA (HR, 1.58 95% CI, 1.17-2.12;
=0.003) and in a subgroup of the overall population with a left ventricular ejection fraction ≤40% (HR, 1.39 95% CI, 1.08-1.81;
=0.01).
Cardiac and noncardiac biomarker abnormalities were common and reflect the complex and multifaceted nature of ATTR-CA, with a wide range of biomarkers remaining independently associated with mortality. Clinical trials are needed to investigate whether biomarker abnormalities represent modifiable risk factors that if specifically targeted could improve outcomes.
Transthyretin cardiac amyloidosis (ATTR-CM) is a progressive and fatal cardiomyopathy. Treatment options in patients with advanced ATTR-CM are limited to cardiac transplantation (CT). Despite case ...series demonstrating comparable outcomes with CT between patients with ATTR-CM and non-amyloid cardiomyopathies, ATTR-CM is considered to be a contraindication to CT in some centers, partly due to a perceived risk of amyloid recurrence in the allograft. We report long-term outcomes of CT in ATTR-CM at two tertiary centers.
We retrospectively evaluated ATTR-CM patients across two tertiary centers who underwent transplantation between 1990 and 2020. Pre-transplantation characteristics were determined and outcomes were compared with a cohort of non-transplanted ATTR-CM patients. Fourteen (12 male, 2 female) patients with ATTR-CM underwent CT including 11 with wild-type ATTR-CM and 3 with variant ATTR-CM (ATTRv). Median age at CT was 62 years and median follow up post-CT was 66 months. One, three, and five-year survival was 100, 92, and 90%, respectively and the longest surviving patient was Censored > 19 years post CT. No patients had recurrence of amyloid in the cardiac allograft. Four patients died, including one with ATTRv-CM from complications of leptomeningeal amyloidosis. Survival among the cohort of patients who underwent CT was significantly prolonged compared to UK patients with ATTR-CM generally (
< 0.001) including those diagnosed under age 65 years (
= 0.008) or with early stage cardiomyopathy (
< 0.001).
CT is well-tolerated, restores functional capacity and improves prognosis in ATTR-CM. The risk of amyloid recurrence in the cardiac allograft appears to be low.
Acute myocardial damage is common in severe COVID-19. Post-mortem studies have implicated microvascular thrombosis, with cardiovascular magnetic resonance (CMR) demonstrating a high prevalence of ...myocardial infarction and myocarditis-like scar. The microcirculatory sequelae are incompletely characterized. Perfusion CMR can quantify the stress myocardial blood flow (MBF) and identify its association with infarction and myocarditis.
To determine the impact of the severe hospitalized COVID-19 on global and regional myocardial perfusion in recovered patients.
A case-control study of previously hospitalized, troponin-positive COVID-19 patients was undertaken. The results were compared with a propensity-matched, pre-COVID chest pain cohort (referred for clinical CMR; angiography subsequently demonstrating unobstructed coronary arteries) and 27 healthy volunteers (HV). The analysis used visual assessment for the regional perfusion defects and AI-based segmentation to derive the global and regional stress and rest MBF.
Ninety recovered post-COVID patients {median age 64 interquartile range (IQR) 54-71 years, 83% male, 44% requiring the intensive care unit (ICU)} underwent adenosine-stress perfusion CMR at a median of 61 (IQR 29-146) days post-discharge. The mean left ventricular ejection fraction (LVEF) was 67 ± 10%; 10 (11%) with impaired LVEF. Fifty patients (56%) had late gadolinium enhancement (LGE); 15 (17%) had infarct-pattern, 31 (34%) had non-ischemic, and 4 (4.4%) had mixed pattern LGE. Thirty-two patients (36%) had adenosine-induced regional perfusion defects, 26 out of 32 with at least one segment without prior infarction. The global stress MBF in post-COVID patients was similar to the age-, sex- and co-morbidities of the matched controls (2.53 ± 0.77 vs. 2.52 ± 0.79 ml/g/min,
=
), though lower than HV (3.00 ± 0.76 ml/g/min,
<
).
After severe hospitalized COVID-19 infection, patients who attended clinical ischemia testing had little evidence of significant microvascular disease at 2 months post-discharge. The high prevalence of regional inducible ischemia and/or infarction (nearly 40%) may suggest that occult coronary disease is an important putative mechanism for troponin elevation in this cohort. This should be considered hypothesis-generating for future studies which combine ischemia and anatomical assessment.
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