Cardiovascular diseases remain a leading cause of global mortality despite advancements in pharmacotherapies, with current treatments facing challenges related to efficacy, tolerability and patient adherence. In response, advanced therapies, such as RNA and gene therapies, have emerged as a promising alternative for addressing both acquired and monogenic cardiovascular conditions. This review explores the current landscape of RNA and gene therapies for cardiovascular disease, focusing on RNA-based therapeutics such as small-interfering RNAs (siRNAs), antisense oligonucleotides and clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9)-based gene editing systems. Recent European Medicines Agency and Food and Drug Administration-approved RNA therapies, including patisiran, vutrisiran and inclisiran, which employ lipid nanoparticle delivery systems, highlight the clinical potential of siRNAs for targeting hepatic molecular pathways. Emerging CRISPR-Cas9 technologies are poised to address genetic mutations at their source, offering permanent correction of pathogenic variants and the potential to treat a broad range of hereditary cardiovascular conditions. Together, these therapies represent a major leap forward in precision medicine, offering long-lasting therapeutic effects and improved patient care and adherence. However, many challenges remain, particularly in targeting such therapies to cardiac tissues and optimising delivery systems. This review discusses the current state of the art in cardiovascular RNA and gene therapies, including current evidence, delivery challenges and the current landscape of gene and RNA therapies in phase I clinical trials and beyond.

Cardiac Magnetic Resonance (CMR) imaging is widely used to personalize heart models for cardiac digital twin analysis because of its ability to visualize soft tissues and capture dynamic functions. However, CMR images have an anisotropic nature, characterized by large inter-slice distances and misalignments from cardiac motion. These limitations result in data loss and measurement inaccuracies, hindering the capture of detailed anatomical structures. In this work, we introduce MorphiNet, a novel network that reproduces heart anatomy learned from high-resolution Computed Tomography (CT) images, unpaired with CMR images. MorphiNet encodes the anatomical structure as gradient fields, deforming template meshes into patient-specific geometries. A multilayer graph subdivision network refines these geometries while maintaining dense point correspondence, suitable for downstream computational analysis. MorphiNet achieved the strongest overall trade-off in bi-ventricular myocardium reconstruction on CMR patients with tetralogy of Fallot, with 0.3 higher Dice score and 2.6 lower Hausdorff distance compared to the best existing template-based methods, while achieving comparable geometric accuracy to neural implicit function methods on CT data at $50\times $ faster inference. Cross-dataset validation on the Automated Cardiac Diagnosis Challenge confirmed robust generalization, achieving a 0.7 Dice score with 30% improvement over previous template-based approaches. We validate our anatomical learning approach through the successful restoration of missing cardiac structures and demonstrate significant improvement over standard Loop subdivision. Motion tracking experiments further confirm MorphiNet's capability for cardiac function analysis, including ejection-fraction estimates that correctly identify myocardial dysfunction in tetralogy of Fallot patients. Code and checkpoints are available at https://github.com/MalikTeng/MorphiNetV2.

Introduction: Aortic stenosis (AS) remains a major cardiovascular condition with substantial unmet clinical need. Valve leaflet fibrosis and calcification drive disease progression, yet the cellular and molecular mechanisms underlying these processes remain incompletely understood. Methods: Single-nucleus RNA-sequencing (snRNA-seq) was performed on biobanked human aortic valves across AS severity. Separately, patients with aortic stenosis and control participants underwent [ 68 Ga]FAPI-46 positron emission tomography (PET) and computed tomography (CT) to quantify fibroblast activation protein (FAP) expressing valvular interstitial cells (VICs) in vivo . Explanted valves from a subset of imaged patients were aligned with in vivo imaging, then partitioned in 5 mm segments for osteocalcin immunohistochemistry and Xenium spatial transcriptomics. Results: snRNA-seq (control n =6, mild/moderate n =8, severe n =11) enabled construction of a cell atlas spanning aortic valve cell populations. A FAP+ VIC subpopulation progressively expanded in association with aortic stenosis disease severity (p=0.026; fig. 1 ). FAP+ VICs showed the highest expression of extracellular matrix genes among VIC subpopulations and were enriched for chondrogenic and osteogenic markers ( POSTN, COL1A2, COMP, CRTAC1, ENPP1 ). [ 68 Ga]FAPI-46 uptake was higher in diseased (n=85) compared with control aortic valves (n=10; p<0.0001; fig. 2 ) and correlated with disease severity (peak aortic jet velocity, r=0.532, p<0.0001) and calcific volume on CT (r=0.487, p<0.001). Tracer-positive valve segments exhibited greater calcific area by osteocalcin immunohistochemistry than tracer-negative segments from the same patient (n=13, 68 segments; negative: 678±159 mm 2 , positive: 2,020±323 mm 2 , p=0.007). Single-cell spatial transcriptomics identified a cellular microenvironment (niche) comprising FAP+ VICs and macrophages localised to calcific borders and enriched in patient-matched-segments with higher tracer uptake (n=4, 9 segments; fig. 3 ). Conclusion: FAP+ VIC accumulation is associated with aortic stenosis disease severity and shows enrichment of extracellular matrix-associated and osteogenic marker genes. [ 68 Ga]FAPI-46 PET identifies FAP-associated signal in vivo that correlates with CT-defined calcification, while matched spatial transcriptomics localises this signal to peri-calcific cellular niches within the valve. FAP+ VICs represent both a disease marker and a promising therapeutic target in aortic stenosis.

Aims: Circulating total desmosine, representing endogenous systemic elastin degradation activity, is an emerging biomarker for mortality risk in several diseases and aging. However, the existing analytical method takes more than 23 hours to complete, limiting its potential applications. The objective of this study was to shorten the turnover time of a stable isotope dilution liquid chromatogram mass spectrometry-based desmosine assay. Materials & methods: Plasma samples were analyzed using acid hydrolysis followed by solid-phase extraction and LC-MS. Two approaches to reduce assay time were tested: microwave-assisted acid hydrolysis and direct injection following solid-phase extraction. Results: The combination of acid hydrolysis at 180 degrees C for 8 minutes and a low-volume elution design for solid-phase extraction reduced the overall assay time to similar to 30 minutes. The assay was validated with intra-day precision and accuracy ranging from 4% to 14%, and -7% to 9%, respectively, while inter-day precision and accuracy were 0% to 9% and 1% to 3%, respectively. The assay was tested in a cohort of patients with acute aortic dissection and control subjects, where desmosine concentrations were approximately three-fold higher in patients. Conclusions: These results demonstrated that rapid desmosine analysis can be achieved with the use of both microwave-assisted hydrolysis and streamlined solid-phase extraction.

Background The Scottish Computed Tomography of the Heart (SCOT-HEART) trial demonstrated that management guided by coronary CT angiography (CCTA) improved the diagnosis, management, and outcome of patients with stable chest pain. We aimed to assess whether CCTA-guided care results in sustained long-term improvements in management and outcomes. Methods SCOT-HEART was an open-label, multicentre, parallel group trial for which patients were recruited from 12 outpatient cardiology chest pain clinics across Scotland. Eligible patients were aged 18-75 years with symptoms of suspected stable angina due to coronary heart disease. Patients were randomly assigned (1:1) to standard of care plus CCTA or standard of care alone. In this prespecified 10-year analysis, prescribing data, coronary procedural interventions, and clinical outcomes were obtained through record linkage from national registries. The primary outcome was coronary heart disease death or non-fatal myocardial infarction on an intention-to-treat basis. This trial is registered at ClinicalTrials.gov (NCT01149590) and is complete. Findings Between Nov 18, 2010, and Sept 24, 2014, 4146 patients were recruited (mean age 57 years [SD 10], 2325 [561%] male, 1821 [439%] female), with 2073 randomly assigned to standard care and CCTA and 2073 to standard care alone. After a median of 100 years (IQR 93-110), coronary heart disease death or non-fatal myocardial infarction was less frequent in the CCTA group compared with the standard care group (137 [66%] vs 171 [82%]; hazard ratio [HR] 079 [95% CI 063-099], p=0044). Rates of all-cause, cardiovascular, and coronary heart disease death, and non-fatal stroke, were similar between the groups (p>005 for all), but non-fatal myocardial infarctions (90 [43%] vs 124 [60%]; HR 072 [055-094], p=0017) and major adverse cardiovascular events (172 [83%] vs 214 [103%]; HR 080 [065-097], p=0026) were less frequent in the CCTA group. Rates of coronary revascularisation procedures were similar (315 [152%] vs 318 [153%]; HR 100 [086-117], p=099) but preventive therapy prescribing remained more frequent in the CCTA group (831 [559%] of 1486 vs 728 [490%] of 1485 patients with available data; odds ratio 117 [95% CI 101-136], p=0034). Interpretation After 10 years, CCTA-guided management of patients with stable chest pain was associated with a sustained reduction in coronary heart disease death or non-fatal myocardial infarction. Identification of coronary atherosclerosis by CCTA improves long-term cardiovascular disease prevention in patients with stable chest pain. Copyright (c) 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

Background:Current guidelines recommend a strategy of clinical surveillance (CS) for patients with asymptomatic severe aortic stenosis and normal left ventricular ejection fraction. Methods:PubMed, Embase, and ClinicalTrials.gov were searched through November 2024 for randomized controlled trials (RCTs) and observational studies comparing surgical aortic valve replacement or transcatheter aortic valve replacement with CS in patients with asymptomatic severe aortic stenosis. Results:Sixteen eligible studies (12 observational studies and 4 RCTs) were identified, with a total of 3919 patients in the observational studies and 1427 patients in the RCTs. In the pooled analyses combining observational studies and RCTs, aortic valve replacement (AVR) was associated with significantly reduced all-cause mortality (incidence rate ratio [IRR], 0.42; 95% CI, 0.31-0.58; P < .01; I 2 = 72%), cardiovascular mortality (IRR, 0.46; 95% CI, 0.28-0.78; P < .01; I 2 = 68%), and unplanned cardiovascular or heart failure (HF)-related hospitalization (IRR, 0.34; 95% CI, 0.21-0.55; P < .01; I 2 = 50%). In 12 observational studies, AVR was associated with significantly lower rates of all-cause mortality (IRR, 0.36; 95% CI, 0.27-0.49; P < .01; I 2 = 65%), and cardiovascular mortality (IRR, 0.33; 95% CI, 0.16-0.70; P < .01; I 2 = 71%) compared with CS. In 4 RCTs, there was no significant difference in all-cause or cardiovascular mortality, but AVR was associated with a significant reduction in unplanned cardiovascular or HF hospitalization (IRR, 0.42; 95% CI, 0.26-0.65; P < .01; I 2 = 27%) and stroke (IRR, 0.63; 95% CI, 0.40-0.98; P = .04; I 2 = 0%). Conclusions:Data from observational studies and recent RCTs suggest that a strategy of preemptive AVR is associated with improved survival and lower rates of unplanned cardiovascular or HF-related hospitalizations and stroke compared to CS.

Aims Vascular calcification is the abnormal deposition of calcium phosphates within blood vessels. This condition is significantly associated with the development of cardiovascular disease, yet the underlying mechanisms remain largely unknown. MicroRNAs (miRNAs) may be crucial in initiating vascular calcification by regulating a network of specific cellular targets. In this study, we explored for the first time the potential role of microRNA-26b (miR-26b) in vascular calcification.Methods and results Using micro-positron emission tomography and computed tomography (micro-PET/CT) imaging with 18F-sodium fluoride, we measured aortic calcification in miR-26b knockout mice (miR-26bKO). We conducted bulk RNA sequencing (RNA-seq), single-cell RNA sequencing, and network analysis to identify cell-specific targets and the cellular complexity contributing to the observed phenotype. Additionally, we examined aortic tissues from patients with aortic aneurysm or valvular-related aortopathy to determine how the expression levels of miR-26b and its targets correlate with calcification. Our findings revealed that miR-26b is downregulated in the aortic tissues of patients with aortic calcification, whereas miR-26b expression negatively correlates with calcification levels. Similarly, miR-26bKO mice developed spontaneous age-related aortic microcalcifications. Combining single-cell transcriptomics with network analyses, we identified and mapped cell-type specific targets of miR-26b and regulatory pathways. Furthermore, we validated the cell-specific expression of Smad1 in smooth muscle cells (SMCs) and characterized the cell-cell communication between aortic cells, exposing the bone morphogenetic protein (BMP) pathway. The development of microcalcification was attributed to Bmp4 released from fibroblasts (FBLs), leading to Smad1 phosphorylation and calcium accumulation in SMCs of miR-26bKO mice. We found that aortic microcalcification could be pharmacologically reversed by disrupting cellular communication. Lastly, we demonstrated an inverse correlation between miR-26b and SMAD1 levels in calcified aortic tissues.Conclusion The deficiency of miR-26b is crucial for initiating and promoting aortic calcification, revealing new therapeutic targets for aortic disease.

Importance Myocardial fibrosis in aortic stenosis (AS) may exhibit sex differences. However, its prognostic significance in women with AS remains unclear. Objective To investigate sex differences in myocardial fibrosis assessed by cardiovascular magnetic resonance (CMR) and evaluate its prognostic value in women and men with AS. Design, Setting, and Participants Patients with severe AS who underwent CMR before aortic valve replacement (AVR) were prospectively enrolled from 13 international sites between March 2011 and September 2021. Myocardial fibrosis was evaluated using extracellular volume fraction (ECV%) and late gadolinium enhancement (LGE). The main analysis was conducted on patients without obstructive coronary artery disease (CAD), defined as those with no history of myocardial infarction and no concomitant coronary artery bypass grafting. Data were analyzed from December 2023 to February 2024. Exposures Surgical or transcatheter AVR. Main Outcomes and Measures The primary outcome was post–AVR all-cause mortality and the secondary outcome was cardiovascular mortality. Results Of 822 patients, 670 were without obstructive CAD (368 men [55%] and 302 women [45%]). Among these, women and men had a similar age (median, 72 years vs 71 years, respectively), comorbidities, and AS severity. ECV% was similar between sexes; however, women had less LGE (both infarct and noninfarct LGE). After a median follow-up of 3.7 (IQR, 2.1-4.7) years, there were 76 deaths (11.3%), including 29 adjudicated cardiovascular deaths, in patients without obstructive CAD. Increasing ECV% and LGE were associated with higher all-cause and cardiovascular mortality in both sexes. Cox analyses demonstrated that both ECV% and LGE were associated with higher all-cause mortality without significant interaction by sex (women: adjusted hazard ratio [HR], 1.08 per 1% ECV% increase; 95% CI, 1.04-1.12; P < .001; men: adjusted HR, 1.01; 95% CI, 0.96-1.06; P = .66; P for interaction by sex = .09 and women: adjusted HR, 2.49 for the presence of LGE; 95% CI, 1.07-5.80; P = .03; men: adjusted HR, 1.82; 95% CI, 1.00-3.32; P = .04; P for interaction by sex = .68). In the entire population (n = 822), both noninfarct and infarct-related LGE were associated with increased mortality without significant interaction by sex. Conclusions and Relevance In this study, patients with severe AS who underwent AVR exhibited similar ECV% between sexes, while women had lower LGE. Increased myocardial fibrosis provided important prognostic value for both sexes.

BACKGROUND Coronary computed tomography (CT) angiography-derived attenuation-based plaque burden assessments can identify patients at risk of myocardial infarction. OBJECTIVES This study sought to assess whether more detailed plaque morphology assessment using patient-based radiomic characterization could further enhance the identification of patients at risk of myocardial infarction during longterm follow-up. METHODS Post hoc analysis of coronary CT angiography was performed within the SCOT-HEART (Scottish Computed Tomography of the HEART) clinical trial. Coronary plaque segmentations were used to calculate plaque burdens and eigen radiomic features that described plaque morphology. Univariable and multivariable Cox proportional hazard models were used to evaluate the association between clinical and image-based features and fatal or nonfatal myocardial infarction, whereas Harrell's C-statistic and cumulative/dynamic area under the curve (AUC) values with cross-validation were used to evaluate prognostic performance. RESULTS Scans from 1,750 patients (aged 58 f 9 years; 56% male) were analyzed. Over a median of 8.6 years of follow-up, 82 patients had a fatal or nonfatal myocardial infarction. Among the eigen radiomic features, 15 were associated with myocardial infarction in univariable analysis, and 8 features retained their association following adjustment for cardiovascular risk score and plaque burden metrics. Adding plaque burden metrics to a clinical model incorporating cardiovascular risk score, Agatston score and presence of obstructive coronary artery disease had similar prediction performance (C-statistic 0.70 vs 0.70), whereas further addition of eigen radiomic features improved model performance (C-statistic 0.74). In temporal analysis, the model including eigen radiomic features had higher cumulative/dynamic AUC values following the fifth year of follow-up. CONCLUSIONS Radiomics-based precision phenotyping of coronary plaque morphology provided improvements to long-term prediction of myocardial infarction by CT angiography over and above clinical factors and plaque burden. (Scottish Computed Tomography of the HEART [SCOT-HEART]; NCT01149590) (JACC Cardiovasc Imaging. 2025;18:308-319) (c) 2025 by the American College of Cardiology Foundation.

Aims Models predicting the likelihood of obstructive coronary artery disease (CAD) on invasive coronary angiography exist. However, as stable patients with new-onset chest pain frequently have lower clinical likelihood and preferably undergo index testing by non-invasive tests such as coronary computed tomography angiography (CCTA), clinical likelihood models calibrated against observed obstructive CAD at CCTA are warranted. The aim was to develop CCTA-calibrated risk-factor- and coronary artery calcium score-weighted clinical likelihood models (i.e. RF-CLCCTA and CACS-CLCCTA models, respectively). Methods and results Based on age, sex, symptoms, and cardiovascular risk factors, an advanced machine learning algorithm utilized a training cohort (n = 38 269) of symptomatic outpatients with suspected obstructive CAD to develop both a RF-CLCCTA model and a CACS-CLCCTA model to predict observed obstructive CAD on CCTA. The models were validated in several cohorts (n = 28 340) and compared with a currently endorsed basic pre-test probability (Basic PTP) model. For both the training and pooled validation cohorts, observed obstructive CAD at CCTA was defined as >50% diameter stenosis. Observed obstructive CAD at CCTA was present in 6443 (22.7%) patients in the pooled validation cohort. While the Basic PTP underestimated the prevalence of observed obstructive CAD at CCTA, the RF-CLCCTA and CACS-CLCCTA models showed superior calibration. Compared with the Basic PTP model, the RF-CLCCTA and CACS-CLCCTA models showed superior discrimination (area under the receiver operating curves 0.71 [95% confidence interval (CI) 0.70-0.72] vs. 0.74 (95% CI 0.73-0.75) and 0.87 (95% CI 0.86-0.87), P < 0.001 for both comparisons). Conclusion CCTA-calibrated clinical likelihood models improve calibration and discrimination of observed obstructive CAD at CCTA.

Importance:Healthy lifestyles and uptake of primary preventive therapies for cardiovascular disease remain poor. Objective:To determine the impact of coronary computed tomography (CT) angiography on healthy lifestyle behaviors, acceptance of recommended treatments, and modification of risk factors as compared with guideline-directed cardiovascular risk scoring. Design, Setting, and Participants:This was a nested substudy conducted from September 2020 to August 2024 of a randomized clinical trial where participants underwent cardiovascular risk scoring or coronary CT angiography. Primary care-based screening took place in Scotland. Included in the analysis were asymptomatic individuals aged 40 to 70 years without known cardiovascular disease and with at least 1 cardiovascular risk factor. Study data were analyzed from August to September 2024. Interventions:All participants received lifestyle advice with additional recommendations for moderate-intensity statin therapy if the 10-year cardiovascular risk was greater than or equal to 10% or combined antiplatelet and at least moderate-intensity statin therapies if coronary atherosclerosis was identified on CT angiography. Main Outcomes and Measures:The composite primary outcome was compliance with the National Institute for Health and Care Excellence recommendations for diet, body mass index, smoking, and physical exercise at 6 months. Results:Between September 2020 and January 2024, 400 participants were enrolled (median [IQR] age, 62 [56-65] years; 198 female [49.5%]; median [IQR] 10-year cardiovascular risk, 14% [9%-19%]) with 195 randomized to cardiovascular risk scoring and 205 to coronary CT angiography. At 6 months, those who underwent CT angiography were more likely to meet the primary composite end point (17% [33 of 194 participants] vs 6% [10 of 177 participants]; odds ratio, 3.42; 95% CI, 1.63-6.94; P < .001). Compared with cardiovascular risk scoring, fewer participants were recommended preventive therapy after CT angiography (51% [105 of 205 participants] vs 75% [147 of 195 participants]; P < .001), but acceptance of recommendations was higher (77% [81 of 105 participants] vs 46% [68 of 147 participants]; P < .001). This resulted in similar use of lipid-lowering therapy (44% [90 of 205 participants] vs 35% [69 of 195 participants]; OR, 1.43; 95% CI, 0.96-2.15; P = .08) and greater use of antiplatelet therapy in those randomized to CT angiography (40% [83 of 205 participants] vs 0.5% [1 of 195 participants]; P < .001). Participants randomized to coronary CT angiography had small incremental improvements in risk factors and 10-year cardiovascular risk, largely driven by those with CT-defined coronary atheroma. Conclusions and Relevance:Results of this cohort study reveal that compared with cardiovascular risk scoring, coronary CT angiography was associated with modest improvements in healthier lifestyle behaviors, acceptance of recommended preventive therapy, and risk factor modification. Whether this strategy reduces coronary events remains to be established.

The development of the first total-body positron emission tomography (PET) clinical scanner is a transformational moment in nuclear medicine, reigniting the field by tackling 2 long-standing and critical barriers to the widespread clinical use of PET: radiation dose and patient throughput. Total-body PET also provides several other unique research and clinical opportunities, including potential to streamline radiotracer discovery and development pipelines. PET does not exist without radiotracers. However, despite decades of radiotracer development programs, the number of successful PET radiotracers adopted and approved for human use is extremely low. In neurology, an important area for nuclear medicine, only approximately 4% of all novel radiotracers that survive the radiotracer translational "valley of death" are adopted clinically. The potential for total-body PET technology to reverse these low numbers of radiotracer development and adoption is high. This will require the PET community to come together with the regulators to chart new frameworks for radiotracer development and translational pipelines. This article will discuss which stages of the radiotracer discovery pipeline can benefit most from the recent development of total-body PET technology. It will review the latest key developments in radiochemistry modernization and describe how these could ameliorate regulatory hurdles and deliver the groundbreaking potential of total-body PET. Finally, this article will highlight emerging radiotracer discovery opportunities that could be rapidly facilitated by total-body PET. SIGNIFICANCE STATEMENT: In addition to creating new opportunities for clinical research and patient care, total-body positron emission tomography technology can also embolden radiochemistry modernization in the clinic and break long-standing translational barriers encountered during radiotracer discovery pipelines.

Computed tomography coronary angiography provides a non-invasive evaluation of coronary artery disease that includes phenotyping of atherosclerotic plaques and the surrounding perivascular adipose tissue (PVAT). Image analysis techniques have been developed to quantify atherosclerotic plaque burden and morphology as well as the associated PVAT attenuation, and emerging radiomic approaches can add further contextual information. PVAT attenuation might provide a novel measure of vascular health that could be indicative of the pathogenetic processes implicated in atherosclerosis such as inflammation, fibrosis or increased vascularity. Bidirectional signalling between the coronary artery and adjacent PVAT has been hypothesized to contribute to coronary artery disease progression and provide a potential novel measure of the risk of future cardiovascular events. However, despite the development of more advanced radiomic and artificial intelligence-based algorithms, studies involving large datasets suggest that the measurement of PVAT attenuation contributes only modest additional predictive discrimination to standard cardiovascular risk scores. In this Review, we explore the pathobiology of coronary atherosclerotic plaques and PVAT, describe their phenotyping with computed tomography coronary angiography, and discuss potential future applications in clinical risk prediction and patient management. In this Review, Dey and colleagues explore the pathobiology of coronary atherosclerotic plaques and perivascular adipose tissue, describe their phenotyping with computed tomography coronary angiography, and discuss potential future applications in clinical risk prediction and patient management.

AIMS:To investigate whether the PROMISE Minimal Risk Score (PMRS) enables adjustment of the risk factor-weighted clinical likelihood of obstructive CAD. METHODS AND RESULTS:Two cohorts of stable patients with new-onset chest pain were established: a diagnosis cohort (n = 4,298) and a prognosis cohort (n = 14,013). Patients were stratified by the risk factor-weighted clinical likelihood model, and patients with low (>5 to 15%) clinical likelihood were further stratified by the PMRS using a ≥ 34% cut-off. For the diagnosis cohort, obstructive CAD was defined invasively by fractional flow reserve ≤0.80. For the prognosis cohort, the primary endpoint was non-fatal myocardial infarction or all-cause death.In the diagnosis cohort, 1,669 (39%) patients had low (>5 to ≤15%) clinical likelihood, of whom 301/1,669 (18%) patients had a PMRS ≥34%. In these patients, the prevalence of obstructive CAD was 14/301 (4.7%), similar to patients with very-low (≤5%) clinical likelihood [64/1,667 (3.8%), p = 0.21]. In the prognosis cohort, 6,187 (44%) patients had low (>5 to ≤15%) clinical likelihood, of whom 993/6,187 (16%) patients had a PMRS ≥34%. In these patients, event rates were similar to patients with very-low (≤5%) clinical likelihood [hazard ratio, 0.91 (95% confidence interval, 0.52-1.52), p = 0.77]. Compared to patients with low (>5 to ≤15%) clinical likelihood and a PMRS <34%, the prevalence of obstructive CAD and risk were lower in patients with low (>5 to ≤15%) clinical likelihood and a PMRS ≥34% (p < 0.01 for both comparisons). CONCLUSION:In patients with low (>5 to ≤15%) clinical likelihood of obstructive CAD, the PMRS enables safe down-classification of 1 in 6 patients to a very-low (≤5%) clinical likelihood category. CLINICAL TRIAL REGISTRATION:Clinicaltrials.gov identifiers: NCT02264717, NCT03481712, NCT04707859, NCT01174550 and NCT01149590.

18F-sodium fluoride (18F-NaF) positron emission tomography (PET) detects active microcalcification and predicts adverse outcomes including bioprosthetic valve deterioration. However, measuring small areas of 18F-NaF uptake within moving structures remains challenging, requiring further optimization. We developed a representative cardiac phantom to optimize 18F-NaF imaging of bioprosthetic valves. We placed a bioprosthetic valve with two pockets sutured to the leaflets mimicking valvular lesions and a subvalvular ring mimicking the valve remnant into the phantom and injected each with 18F-radionuclide (1 μCi pockets, 4 μCi ring). We injected the cardiac chambers with iohexol and 18F-radionuclide (0.176 mCi) for background activity. PET and computed tomography (CT) images were acquired using a Siemens Biograph Vision high-resolution digital PET/CT scanner. We analysed target-to-background ratio (TBR) and signal-to-noise ratio (SNR) and subjective measures of image quality. We compared results with a human case of transcatheter aortic valve replacement. Initially the SNR and TBR in the phantom greatly exceeded those from human imaging. We reduced the scan duration used for reconstruction to 30 and 15 s, achieving comparable results (30 s vs. 15 s vs. patient: SNR 45.6 vs. 13.9 vs. 44.3, TBRmax 6.5 vs. 5.4 vs. 4.1, noise 10.2% vs. 8.8% vs. 12.0%). With motion correction, SNR and image quality improved in the phantom (30 s 135.8 vs. 45.6, 15 s 32.9 vs. 13.9) but remained similar in the human case (47.3 vs. 44.3). A cardiac phantom can mimic clinical 18F-NaF valve bioprosthesis imaging, providing an opportunity to explore acquisition, reconstruction, and post-processing of 18F-NaF PET/CT for small mobile cardiac structures.

In the past decade, there has been substantive progress in gene therapy across disease indications. However, despite multiple gene therapies being approved for clinical use, none have a cardiovascular indication. Several reasons for this have inhibited or delayed progress in the cardiovascular field. First, developing cardiovascular gene therapeutics represents a substantial technical challenge, particularly relating to identifying and building effective delivery systems for therapeutic cargo that will be sufficient to gain meaningful efficacy with acceptable safety for the patient. Second, for genetic disease, gene editing therapy of pathogenic variants is at a relatively early stage of development. Third, since this is a field in development, the optimal design of clinical trials of cardiovascular gene therapies is also evolving and requires expert attention. Despite this, recent and current clinical trials are charting new ground, gaining valuable new patient-focused information that provides critical new learning and bench-to-bedside iterative development that has been so successful in other disease areas. While most clinical trials currently focus on cardiac gene therapy, vascular approaches are being developed, both genetic and common. We herein review the state-of-the-art in this rapidly progressing field of study. We consider gene therapy vector design, including transcriptional control, an area of incredible opportunity through engineering biology approaches to design, build, and test bespoke transcriptional units for expression of therapeutic cargo. Achieving progress in this exciting field will require close working between all stakeholders, including academic, clinical, industry, regulatory, and patient communities. Based on current progress, there is a 10-year horizon for bringing several cardiovascular gene therapies to licensing.