Current understanding and management of cardiovascular involvement in rheumatic immune-mediated inflammatory diseases.

Immune-mediated inflammatory diseases (IMIDs) are a spectrum of disorders of overlapping immunopathogenesis, with a prevalence of up to 10% in Western populations and increasing incidence in developing countries. Although targeted treatments have revolutionized the management of rheumatic IMIDs, cardiovascular involvement confers an increased risk of mortality and remains clinically under-recognized. Cardiovascular pathology is diverse across rheumatic IMIDs, ranging from premature atherosclerotic cardiovascular disease (ASCVD) to inflammatory cardiomyopathy, which comprises myocardial microvascular dysfunction, vasculitis, myocarditis and pericarditis, and heart failure. Epidemiological and clinical data imply that rheumatic IMIDs and associated cardiovascular disease share common inflammatory mechanisms. This concept is strengthened by emergent trials that indicate improved cardiovascular outcomes with immune modulators in the general population with ASCVD. However, not all disease-modifying therapies that reduce inflammation in IMIDs such as rheumatoid arthritis demonstrate equally beneficial cardiovascular effects, and the evidence base for treatment of inflammatory cardiomyopathy in patients with rheumatic IMIDs is lacking. Specific diagnostic protocols for the early detection and monitoring of cardiovascular involvement in patients with IMIDs are emerging but are in need of ongoing development. This Review summarizes current concepts on the potentially targetable inflammatory mechanisms of cardiovascular pathology in rheumatic IMIDs and discusses how these concepts can be considered for the diagnosis and management of cardiovascular involvement across rheumatic IMIDs, with an emphasis on the potential of cardiovascular imaging for risk stratification, early detection and prognostication.

Diffuse Interstitial Fibrosis of the Myocardium Predicts Outcome in Moderate and Asymptomatic Severe Aortic Stenosis.

BACKGROUND: Patients with moderate or asymptomatic severe aortic stenosis (AS) are at risk of cardiovascular events. OBJECTIVES: The authors investigated the utility of cardiac magnetic resonance (CMR) to identify drivers of outcome in patients with moderate or asymptomatic severe AS. METHODS: A prospective, international, multicenter cohort (n = 457) of patients with moderate (aortic valve area [AVA]: 1.0-1.5 cm2) or asymptomatic severe AS (AVA ≤1.0 cm2 and NYHA functional class I-II) patients underwent CMR. Diffuse interstitial fibrosis and scar in the myocardium were analyzed with extracellular volume fraction (ECV%) and late gadolinium enhancement (LGE). The outcome was a composite of mortality and heart failure admission. RESULTS: Median ECV% was 26.6% (IQR: 24.4%-29.9%), and LGE was present in 31.5% (median 0.8%; IQR: 0.1%-1.7%). Greater AS severity was associated with greater left ventricular mass and diastolic dysfunction, but not with ECV% or LGE. During a median 5.7 years of follow-up, 83 events occurred. Patients with events had higher ECV% (median ECV% 26.3% vs 28.2%; P = 0.003). Patients in the highest ECV% tertiles (ECV% >28.6%) had worse outcomes both in the entire cohort and in those with NYHA functional class I moderate or severe AS, and ECV% was independently associated with outcome (adjusted HR: 1.05; P = 0.039). The ECV% had significant incremental prognostic value when added to parameters of AS severity and cardiac function, comorbidities, aortic valve replacement, and LGE (P < 0.05). CONCLUSIONS: Increased diffuse interstitial fibrosis of the myocardium is associated with poor outcomes in patients with moderate and asymptomatic severe AS and can help identify those who require closer surveillance for adverse outcomes.

Effect of Denosumab or Alendronate on Vascular Calcification: Secondary Analysis of SALTIRE2 Randomized Controlled Trial.

BACKGROUND: Patients with osteoporosis demonstrate increased vascular calcification but the effect of osteoporosis treatments on vascular calcification remains unclear. The present study aimed to examine whether coronary or aortic calcification are influenced by denosumab and alendronic acid treatment. METHODS AND RESULTS: In a double-blind randomized controlled SALTIRE2 (Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis) trial, patients with aortic stenosis were randomized 2:1:2:1 to denosumab, placebo injection, alendronic acid, or placebo capsule. Participants underwent serial imaging with computed tomography and 18F-sodium fluoride positron emission tomography for the assessment of vascular calcium burden and calcification activity, respectively. We report the prespecified secondary analyses of 24-month change in coronary calcium score, and 12-month changes in thoracic aorta calcium score, coronary and aortic 18F-sodium fluoride activity. One hundred fifty patients with aortic stenosis (72±8 years; 21% female) were randomized to denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25). There were no differences in change in coronary calcium scores between placebo (16 [-64 to 148] Agatston units) and either denosumab (94 [0-212] Agatston units, P=0.24) or alendronic acid (34 [-62 to 134], P=0.99). There were no differences in change in thoracic aorta calcium scores between placebo (132 [22-512] Agatston units) and either denosumab (118 [11-340], P=0.75) or alendronic acid (116 [26-498] Agatston units, P=0.62). There were no differences in changes in coronary or aortic 18F-sodium fluoride activity between treatment groups. CONCLUSIONS: Neither alendronic acid nor denosumab are associated with changes in the activity or progression of coronary or aortic calcification. Osteoporosis treatments do not appear to have major impact on vascular calcification of atherosclerosis. REGISTRATION: https://www.clinicaltrials.gov; Unique identifier: NCT02132026.

Interleukin 6 plasma levels are associated with progression of coronary plaques.

BACKGROUND: Inflammation plays a pivotal role in atherogenesis and is a causal risk factor for atherosclerotic cardiovascular disease. Non-invasive coronary CT angiography (CCTA) enables evaluation of coronary plaque phenotype. This study investigates the relationship between a comprehensive panel of inflammatory markers and short-term plaque progression on serial CCTA imaging, hypothesising that inflammation is associated with increased plaque volume. METHODS: A total of 161 patients aged ≥40 years with stable multivessel coronary artery disease were included, who underwent CCTA at baseline and 12 months follow-up. Baseline plasma levels of interleukin 6 (IL-6), high-sensitivity C-reactive protein and other inflammatory markers were measured. Plaque volumes were assessed using semiautomated software, calculating total, noncalcified, calcified and low-attenuation noncalcified plaque volumes. Linear regression models, adjusted for ASSIGN score, segment involvement score and body mass index, evaluated associations between inflammatory markers and plaque volume changes. RESULTS: The mean±SD age was 65.4±8.4 years, with 129 (80.6%) male participants. Baseline total plaque volume was 1394 (1036, 1993) mm³. After 12 months, total plaque volume changed by 78 (-114, 244) mm³. IL-6 levels were associated with a 4.9% increase in total plaque volume (95% CI: 0.9 to 8.9, p=0.018) and a 4.8% increase in noncalcified plaque volume (95% CI: 0.7 to 8.9, p=0.022). No significant associations were observed for other inflammatory markers. CONCLUSIONS: Plasma IL-6 levels are significantly associated with increased total and noncalcified short-term plaque progression in patients with stable coronary artery disease. This supports the potential of IL-6 as a target for reducing plaque progression and cardiovascular risk.

Deep Learning Model of Diastolic Dysfunction Risk Stratifies the Progression of Early-Stage Aortic Stenosis.

BACKGROUND: The development and progression of aortic stenosis (AS) from aortic valve (AV) sclerosis is highly variable and difficult to predict. OBJECTIVES: The authors investigated whether a previously validated echocardiography-based deep learning (DL) model assessing diastolic dysfunction (DD) could identify the latent risk associated with the development and progression of AS. METHODS: The authors evaluated 898 participants with AV sclerosis from the ARIC (Atherosclerosis Risk In Communities) cohort study and associated the DL-predicted probability of DD with 2 endpoints: 1) the new diagnosis of AS; and 2) the composite of subsequent mortality or AV interventions. Validation was performed in 2 additional cohorts: 1) in 50 patients with mild-to-moderate AS undergoing cardiac magnetic resonance (CMR) imaging and serial echocardiographic assessments; and 2) in 18 patients with AV sclerosis undergoing 18F-sodium fluoride (NaF) and 18F-fluorodeoxyglucose positron emission tomography (PET) combined with computed tomography (CT) to assess valvular inflammation and calcification. RESULTS: In the ARIC cohort, a higher DL-predicted probability of DD was associated with the development of AS (adjusted HR: 3.482 [95% CI: 2.061-5.884]; P < 0.001) and subsequent mortality or AV interventions (adjusted HR: 7.033 [95% CI: 3.036-16.290]; P < 0.001). The multivariable Cox model (incorporating the DL-predicted probability of DD) derived from the ARIC cohort efficiently predicted the progression of AS (C-index: 0.798 [95% CI: 0.648-0.948]) in the CMR cohort. Moreover, the predictions of this multivariable Cox model correlated positively with valvular 18F-NaF mean standardized uptake values in the PET/CT cohort (r = 0.62; P = 0.008). CONCLUSIONS: Assessment of DD using DL can stratify the latent risk associated with the progression of early-stage AS.

Clinical Significance of Myocardial Injury in Patients Hospitalized for COVID-19: A Prospective, Multicenter, Cohort Study.

BACKGROUND: Hospitalized COVID-19 patients with troponin elevation have a higher prevalence of cardiac abnormalities than control individuals. However, the progression and impact of myocardial injury on COVID-19 survivors remain unclear. OBJECTIVES: This study sought to evaluate myocardial injury in COVID-19 survivors with troponin elevation with baseline and follow-up imaging and to assess medium-term outcomes. METHODS: This was a prospective, longitudinal cohort study in 25 United Kingdom centers (June 2020 to March 2021). Hospitalized COVID-19 patients with myocardial injury underwent cardiac magnetic resonance (CMR) scans within 28 days and 6 months postdischarge. Outcomes were tracked for 12 months, with quality of life surveys (EuroQol-5 Dimension and 36-Item Short Form surveys) taken at discharge and 6 months. RESULTS: Of 342 participants (median age: 61.3 years; 71.1% male) with baseline CMR, 338 had a 12-month follow-up, 235 had a 6-month CMR, and 215 has baseline and follow-up quality of life surveys. Of 338 participants, within 12 months, 1.2% died; 1.8% had new myocardial infarction, acute coronary syndrome, or coronary revascularization; 0.8% had new myopericarditis; and 3.3% had other cardiovascular events requiring hospitalization. At 6 months, there was a minor improvement in left ventricular ejection fraction (1.8% ± 1.0%; P < 0.001), stable right ventricular ejection fraction (0.4% ± 0.8%; P = 0.50), no change in myocardial scar pattern or volume (P = 0.26), and no imaging evidence of continued myocardial inflammation. All pericardial effusions (26 of 26) resolved, and most pneumonitis resolved (95 of 101). EuroQol-5 Dimension scores indicated an overall improvement in quality of life (P < 0.001). CONCLUSIONS: Myocardial injury in severe hospitalized COVID-19 survivors is nonprogressive. Medium-term outcomes show a low incidence of major adverse cardiovascular events and improved quality of life. (COVID-19 Effects on the Heart; ISRCTN58667920).

Quantitative Computed Tomography Angiography for the Evaluation of Valvular Fibrocalcific Volume in Aortic Stenosis.

BACKGROUND: Aortic stenosis (AS) is characterized by calcification and fibrosis. The ability to quantify these processes simultaneously has been limited with previous imaging methods. OBJECTIVES: The purpose of this study was to evaluate the aortic valve fibrocalcific volume by computed tomography (CT) angiography in patients with AS, in particular, to assess its reproducibility, association with histology and disease severity, and ability to predict/track progression. METHODS: In 136 patients with AS, fibrocalcific volume was calculated on CT angiograms at baseline and after 1 year. CT attenuation distributions were analyzed using Gaussian-mixture-modeling to derive thresholds for tissue types enabling the quantification of calcific, noncalcific, and fibrocalcific volumes. Scan-rescan reproducibility was assessed and validation provided against histology and in an external cohort. RESULTS: Fibrocalcific volume measurements took 5.8 ± 1.0 min/scan, demonstrating good correlation with ex vivo valve weight (r = 0.51; P < 0.001) and excellent scan-rescan reproducibility (mean difference -1%, limits of agreement -4.5% to 2.8%). Baseline fibrocalcific volumes correlated with mean gradient on echocardiography in both male and female participants (rho = 0.64 and 0.69, respectively; both P < 0.001) and in the external validation cohort (n = 66, rho = 0.58; P < 0.001). The relationship was driven principally by calcific volume in men and fibrotic volume in women. After 1 year, fibrocalcific volume increased by 17% and correlated with progression in mean gradient (rho = 0.32; P = 0.003). Baseline fibrocalcific volume was the strongest predictor of subsequent mean gradient progression, with a particularly strong association in female patients (rho = 0.75; P < 0.001). CONCLUSIONS: The aortic valve fibrocalcific volume provides an anatomic assessment of AS severity that can track disease progression precisely. It correlates with disease severity and hemodynamic progression in both male and female patients.

Lipoprotein(a) and Calcific Aortic Valve Stenosis Progression: A Systematic Review and Meta-Analysis.

Importance: There are currently no pharmacological treatments available to slow hemodynamic progression of aortic stenosis. Plasma lipoprotein(a) concentrations predict incident aortic stenosis but its association with hemodynamic progression is controversial. Objective: To determine the association between plasma lipoprotein(a) concentrations and hemodynamic progression in patients with aortic stenosis. Design, Settings and Participants: The study included patients with aortic stenosis from 5 longitudinal clinical studies conducted from March 2001 to March 2023 in Canada and the UK. Of 757 total patients, data on plasma lipoprotein(a) concentrations and rates of hemodynamic progression assessed by echocardiography were available for 710, who were included in this analysis. Data were analyzed from March 2023 to April 2024. Exposure: Cohort-specific plasma lipoprotein(a) concentration tertiles. Main Outcomes and Measures: Hemodynamic aortic stenosis progression on echocardiography as assessed by annualized change in peak aortic jet velocity, mean transvalvular gradient, and aortic valve area. Results: Among the included patients, 497 (70%) were male and 213 (30%) were female. The mean (SD) age was 65.2 (13.1) years. Patients in the top lipoprotein(a) tertile demonstrated 41% (estimate, 1.41; 95% CI, 1.13-1.75) faster progression of peak aortic jet velocity and 57% (estimate, 1.57; 95% CI, 1.18-2.10) faster progression of mean transvalvular gradient than patients in the bottom tertile. There was no evidence of heterogeneity across the individual cohorts. Progression of aortic valve area was comparable between groups (estimate, 1.23; 95% CI, 0.71-2.12). Similar results were observed when plasma lipoprotein(a) concentrations were treated as a continuous variable. Conclusions and Relevance: In this study, higher plasma lipoprotein(a) concentrations were associated with faster rates of hemodynamic progression in patients with aortic stenosis. Lowering plasma lipoprotein(a) concentrations warrants further investigation in the prevention and treatment of aortic stenosis.

Rationale and Design of SCOT-HEART 2 Trial: CT Angiography for the Prevention of Myocardial Infarction.

Coronary artery disease continues to be the leading cause of death globally. Identifying patients who are at risk of coronary artery disease remains a public health priority. At present, the focus of cardiovascular disease prevention relies heavily on probabilistic risk scoring despite no randomized controlled trials demonstrating their efficacy. The concept of using imaging to guide preventative therapy is not new, but has previously focused on indirect measures such as carotid intima-media thickening or coronary artery calcification. In recent trials, patients found to have coronary artery disease on computed tomography (CT) coronary angiography were more likely to be started on preventative therapy and had lower rates of cardiac events. This led to the design of the SCOT-HEART 2 (Scottish Computed Tomography of the Heart 2) trial, which aims to determine whether screening with the use of CT coronary angiography is more clinically effective than cardiovascular risk scoring to guide the use of primary preventative therapies and reduce the risk of myocardial infarction.

Systematic hand-held echocardiography in patients hospitalized with acute coronary syndrome.

AIMS: Transthoracic echocardiography is recommended in all patients with acute coronary syndrome but is time-consuming and lacks an evidence base. We aimed to assess the feasibility, diagnostic accuracy, and time efficiency of hand-held echocardiography in patients with acute coronary syndrome and describe the impact of echocardiography on clinical management in this setting. METHODS AND RESULTS: Patients with acute coronary syndrome underwent both hand-held and transthoracic echocardiographies with agreement between key imaging parameters assessed using kappa statistics. The immediate clinical impact of hand-held echocardiography in this population was systematically evaluated. Overall, 262 patients (65 ± 12 years, 71% male) participated. Agreement between hand-held and transthoracic echocardiographies was good-to-excellent (kappa 0.60-1.00) with hand-held echocardiography having an overall negative predictive value of 95%. Hand-held echocardiography was performed rapidly (7.7 ± 1.6 min) and completed a median of 5 (interquartile range 3-20) h earlier than transthoracic echocardiography. Systematic hand-held echocardiography in all patients with acute coronary syndrome identified an important cardiac abnormality in 50%, and the clinical management plan was changed by echocardiography in 42%. In 85% of cases, hand-held echocardiography was sufficient for patient decision-making, and transthoracic echocardiography was no longer deemed necessary. CONCLUSION: In patients with acute coronary syndrome, hand-held echocardiography provides comparable results to transthoracic echocardiography, can be more rapidly applied, and gives sufficient imaging information for decision-making in the vast majority of patients. Systematic echocardiography has clinical impact in half of patients, supporting the clinical utility of echocardiography in this population and providing an evidence base for current guidelines.

Sex differences in coronary atherosclerotic plaque activity using 18F-sodium fluoride positron emission tomography.

INTRODUCTION: There are sex differences in the extent, severity, and outcomes of coronary artery disease. We aimed to assess the influence of sex on coronary atherosclerotic plaque activity measured using coronary 18F-sodium fluoride (18F-NaF) positron emission tomography (PET), and to determine whether 18F-NaF PET has prognostic value in both women and men. METHODS: In a post-hoc analysis of observational cohort studies of patients with coronary atherosclerosis who had undergone 18F-NaF PET CT angiography, we compared the coronary microcalcification activity (CMA) in women and men. RESULTS: Baseline 18F-NaF PET CT angiography was available in 999 participants (151 (15%) women) with 4282 patient-years of follow-up. Compared to men, women had lower coronary calcium scores (116 [interquartile range, 27-434] versus 205 [51-571] Agatston units; p = 0.002) and CMA values (0.0 [0.0-1.12] versus 0.53 [0.0-2.54], p = 0.01). Following matching for plaque burden by coronary calcium scores and clinical comorbidities, there was no sex-related difference in CMA values (0.0 [0.0-1.12] versus 0.0 [0.0-1.23], p = 0.21) and similar proportions of women and men had no 18F-NaF uptake (53.0% (n = 80) and 48.3% (n = 73); p = 0.42), or CMA values > 1.56 (21.8% (n = 33) and 21.8% (n = 33); p = 1.00). Over a median follow-up of 4.5 [4.0-6.0] years, myocardial infarction occurred in 6.6% of women (n = 10) and 7.8% of men (n = 66). Coronary microcalcification activity greater than 0 was associated with a similarly increased risk of myocardial infarction in both women (HR: 3.83; 95% CI:1.10-18.49; p = 0.04) and men (HR: 5.29; 95% CI:2.28-12.28; p < 0.001). CONCLUSION: Although men present with more coronary atherosclerotic plaque than women, increased plaque activity is a strong predictor of future myocardial infarction regardless of sex.

Rationale and design of the early valve replacement in severe asymptomatic aortic stenosis trial.

BACKGROUND: Aortic valve replacement in asymptomatic severe aortic stenosis is controversial. The Early valve replacement in severe ASYmptomatic Aortic Stenosis (EASY-AS) trial aims to determine whether early aortic valve replacement improves clinical outcomes, quality of life and cost-effectiveness compared to a guideline recommended strategy of 'watchful waiting'. METHODS: In a pragmatic international, open parallel group randomized controlled trial (NCT04204915), 2844 patients with severe aortic stenosis will be randomized 1:1 to either a strategy of early (surgical or transcatheter) aortic valve replacement or aortic valve replacement only if symptoms or impaired left ventricular function develop, or other cardiac surgery becomes nessessary. Exclusion criteria include other severe valvular disease, planned cardiac surgery, ejection fraction <50%, previous aortic valve replacement or life expectancy <2 years. The primary outcome is a composite of cardiovascular mortality or heart failure hospitalization. The primary analysis will be undertaken when 663 primary events have accrued, providing 90% power to detect a reduction in the primary endpoint from 27.7% to 21.6% (hazard ratio 0.75). Secondary endpoints include disability-free survival, days alive and out of hospital, major adverse cardiovascular events and quality of life. RESULTS: Recruitment commenced in March 2020 and is open in the UK, Australia, New Zealand, and Serbia. Feasibility requirements were met in July 2022, and the main phase opened in October 2022, with additional international centers in set-up. CONCLUSIONS: The EASY-AS trial will establish whether a strategy of early aortic valve replacement in asymptomatic patients with severe aortic stenosis reduces cardiovascular mortality or heart failure hospitalization and improves other important outcomes.

Coronary Atherosclerotic Plaque Activity and Risk of Myocardial Infarction.

BACKGROUND: Total coronary atherosclerotic plaque activity across the entire coronary arterial tree is associated with patient-level clinical outcomes. OBJECTIVES: We aimed to investigate whether vessel-level coronary atherosclerotic plaque activity is associated with vessel-level myocardial infarction. METHODS: In this secondary analysis of an international multicenter study of patients with recent myocardial infarction and multivessel coronary artery disease, we assessed vessel-level coronary atherosclerotic plaque activity using coronary 18F-sodium fluoride positron emission tomography to identify vessel-level myocardial infarction. RESULTS: Increased 18F-sodium fluoride uptake was found in 679 of 2,094 coronary arteries and 414 of 691 patients. Myocardial infarction occurred in 24 (4%) vessels with increased coronary atherosclerotic plaque activity and in 25 (2%) vessels without increased coronary atherosclerotic plaque activity (HR: 2.08; 95% CI: 1.16-3.72; P = 0.013). This association was not demonstrable in those treated with coronary revascularization (HR: 1.02; 95% CI: 0.47-2.25) but was notable in untreated vessels (HR: 3.86; 95% CI: 1.63-9.10; Pinteraction = 0.024). Increased coronary atherosclerotic plaque activity in multiple coronary arteries was associated with heightened patient-level risk of cardiac death or myocardial infarction (HR: 2.43; 95% CI: 1.37-4.30; P = 0.002) as well as first (HR: 2.19; 95% CI: 1.18-4.06; P = 0.013) and total (HR: 2.50; 95% CI: 1.42-4.39; P = 0.002) myocardial infarctions. CONCLUSIONS: In patients with recent myocardial infarction and multivessel coronary artery disease, coronary atherosclerotic plaque activity prognosticates individual coronary arteries and patients at risk for myocardial infarction.

European Association of Cardiovascular Imaging survey on cardiovascular multimodality imaging in acute myocarditis.

AIMS: To assess the current role of cardiac imaging in the diagnosis, management, and follow-up of patients with acute myocarditis (AM) through a European Association of Cardiovascular Imaging survey. METHODS AND RESULTS: A total of 412 volunteers from 74 countries responded to the survey. Most participants worked in tertiary centres (56%). All participants had access to echocardiography, while 79 and 75% had access to cardiac computed tomography angiography (CCTA) and cardiac magnetic resonance (CMR), respectively. Less than half (47%) had access to myocardial biopsy, and only 5% used this test routinely. CMR was performed within 7 days of presentation in 73% of cases. Non-ischaemic late gadolinium enhancement (LGE, 88%) and high-signal intensity in T2-weighted images (74%) were the most used diagnostic criteria for AM. CCTA was preferred to coronary angiography by 47% of participants to exclude coronary artery disease. Systematic prescription of beta-blockers and angiotensin-converting enzyme inhibitors was reported by 38 and 32% of participants. Around a quarter of participants declared considering LGE burden as a reason to treat. Most participants (90%) reported performing a follow-up echocardiogram, while 63% scheduled a follow-up CMR. The main reason for treatment discontinuation was improvement of left ventricular ejection fraction (89%), followed by LGE regression (60%). In two-thirds of participants, the decision to resume high-intensity sport was influenced by residual LGE. CONCLUSION: This survey confirms the high utilization of cardiac imaging in AM but reveals major differences in how cardiac imaging is used and how the condition is managed between centres, underlining the need for recommendation statements in this topic.