Daily Cardiology Research Analysis

BACKGROUND AND AIMS: The diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) requires advanced imaging, precluding large-scale preclinical testing. Artificial intelligence (AI)-enabled transthoracic echocardiography (TTE) and electrocardiography (ECG) may provide a scalable strategy for preclinical monitoring. METHODS: This was a retrospective analysis of individuals referred for nuclear cardiac amyloid testing at the Yale-New Haven Health System (YNHHS, internal cohort) and Houston Methodist Hospitals (HMH, external cohort). Deep learning models trained to discriminate ATTR-CM from age/sex-matched controls on TTE videos (AI-Echo) and ECG images (AI-ECG) were deployed to generate study-level ATTR-CM probabilities (0%-100%). Longitudinal trends in AI-derived probabilities were examined using age/sex-adjusted linear mixed models, and their discrimination of future disease was evaluated across preclinical stages. RESULTS: Among 984 participants at YNHHS (median age 74 years, 44.3% female) and 806 at HMH (median age 69 years, 34.5% female), 112 (11.4%) and 174 (21.6%) tested positive for ATTR-CM, respectively. Across cohorts and modalities, AI-derived ATTR-CM probabilities from 7352 TTEs and 32 205 ECGs diverged as early as 3 years before diagnosis in cases vs controls (ptime(x)group interaction ≤ .004). Among those with both AI-Echo and AI-ECG probabilities available 1 to 3 years before nuclear testing [n = 433 (YNHHS) sand 174 (HMH)], a double-negative screen at a 0.05 threshold [164 (37.9%) and 66 (37.9%), vs all else] had 90.9% and 85.7% sensitivity (specificity of 40.3% and 41.2%), whereas a double-positive screen [78 (18.0%) and 26 (14.9%), vs all else] had 85.5% and 88.9% specificity (sensitivity of 60.6% and 42.9%). CONCLUSIONS: Artificial intelligence-enabled echocardiography and electrocardiography may enable scalable risk stratification of ATTR-CM during its preclinical course.

KEY POINTS: Magnetic-activated cell sorting–based clustered regularly interspaced short palindromic repeats (CRISPR) screen was used for the first time to identify critical genes and pathways involved in vascular calcification. Epigenetic-focused CRISPR screen identified novel vascular calcification regulators, providing potential targets when integrated with transcriptomics. BACKGROUND: Vascular calcification, mainly driven by osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs), is a common pathologic condition in patients with CKD. However, the roles of other epigenetic regulators in this process remain largely unexplored. Clustered regularly interspaced short palindromic repeats (CRISPR) screen is a highly efficient strategy widely used in identifying genes related to various biologic processes. However, the lack of suitable cell sorting strategies combined with CRISPR screen meant this technology had not been applied to gene screening in vascular calcification. METHODS: We performed an epigenetic-focused CRISPR screen in primary human VSMCs and identified key genes and pathways underlying osteogenic transdifferentiation, based on small guide RNA enrichment in receptor activator of NF-kappa B ligand-positive (calcified) and receptor activator of NF-kappa B ligand-negative (noncalcified) VSMCs isolated by magnetic-activated cell sorting. To validate the screen results, potential genes with different rankings were validated by small interfering RNA intervention and Alizarin Red S staining. Integrating CRISPR results with transcriptome data revealed 17 critical regulators. We further investigated the top hit, anthrax toxin receptor 1 (ANTXR1), in vascular calcification by examining clinical human samples and intervention in mice model. RESULTS: Through CRISPR screen, we identified 122 potential positive-regulating vascular calcification genes and 116 negative-regulating genes. Phenotypic experimental results further verified the roles of genes with different rankings in osteogenic transdifferentiation of VSMCs, reinforcing the validity of our CRISPR screen system. Notably, integrative analysis of CRISPR screen with transcriptome data revealed ANTXR1 as a critical factor regulating vascular calcification. Furthermore, detection of clinical human samples confirmed the upregulation of ANTXR1 during calcification. Knockdown of CONCLUSIONS: Our epigenetic-focused CRISPR screen and transcriptome analysis identified critical epigenetic genes involved in vascular calcification.

AIMS: Radiofrequency renal denervation (RF RDN) safely lowers office and 24-hour blood pressure (BP). This meta-analysis examined the long-term durability of RF RDN based on randomized trials and observational studies. METHODS: Patients with uncontrolled hypertension undergoing RF RDN using the Symplicity Flex™ or Spyral™ device and a minimum follow-up of 3 years were included. Key outcomes included office and 24-hour BP change from baseline as well as changes in antihypertensive drugs. A random effects meta-analysis was conducted through 3 years, or the last reported follow-up beyond 3 years. RESULTS: A total of 2,212 patients identified among 18 reports were evaluated for BP. Mean duration of follow-up was 4.4 years (range 3 to 9.4). The long-term reduction in office systolic BP (OSBP) from baseline in 15 reports (N= 2,040) was -23.0 mmHg (95%CI: -26.8 to -19.1, p<0.05) for the random effects model and -. 24-hour ambulatory systolic BP was available in 11 reports (n=1,018) and decreased significantly by -13.6 mmHg (-16.5 to -10.8, p<0.05). Fixed effect model results were similar. Diastolic office and 24-hr BP paralleled these findings in both models. Nighttime systolic BP also decreased significantly by -14.2 mmHg (-27.6 to -0.8, p<0.05). The number of prescribed antihypertensive drugs and eGFR also decreased. Heart rate remained unchanged through final follow-up in both models. Safety events were rare, with a mean rate of renal artery complication of 0.14% (0.08% to 0.20%). CONCLUSIONS: This meta-analysis comprising 18 studies demonstrated sustained and significant office and ambulatory BP reductions following Symplicity RDN through at least 3 years without an increase in antihypertensive medication. This meta-analysis of 18 studies and over 2000 patients demonstrated sustained and significant office and ambulatory BP reductions following radiofrequency RDN for uncontrolled hypertension through at least 3 years without an increase in antihypertensive medication. office systolic blood pressure decreased by -23.0 mmHg (95%CI: -26.8 to -19.1, p<0.05)24-hour ambulatory systolic blood pressure decreased by -13.6 mmHg (-16.5 to -10.8, p<0.05).