Atherosclerosis is the main underlying cause of cardiovascular diseases. Its prevention is based on the detection and treatment of traditional cardiovascular risk factors¹. However, individuals at risk for early vascular disease often remain unidentified². Recent research has identified new molecules in the pathophysiology of atherosclerosis³, highlighting the need for alternative disease biomarkers and therapeutic targets to improve early diagnosis and therapy efficacy. Here, we observed that imidazole propionate (ImP), produced by microorganisms, is associated with the extent of atherosclerosis in mice and in two independent human cohorts. Furthermore, ImP administration to atherosclerosis-prone mice fed with chow diet was sufficient to induce atherosclerosis without altering the lipid profile, and was linked to activation of both systemic and local innate and adaptive immunity and inflammation. Specifically, we found that ImP caused atherosclerosis through the imidazoline-1 receptor (I1R, also known as nischarin) in myeloid cells. Blocking this ImP–I1R axis inhibited the development of atherosclerosis induced by ImP or high-cholesterol diet in mice. Identification of the strong association of ImP with active atherosclerosis and the contribution of the ImP–I1R axis to disease progression opens new avenues for improving the early diagnosis and personalized therapy of atherosclerosis.

Atherosclerosis is a dynamic process. There is little evidence regarding whether quantification of atherosclerosis extent and progression, particularly in the carotid artery, in asymptomatic individuals predicts all-cause mortality. This study sought to evaluate the independent predictive value (beyond cardiovascular risk factors) of subclinical atherosclerosis burden and progression and all-cause mortality. A population of 5,716 asymptomatic U.S. adults (mean age 68.9 years, 56.7% female) enrolled between 2008 and 2009 in the BioImage (A Clinical Study of Burden of Atherosclerotic Disease in an At Risk Population) study underwent examination by vascular ultrasound to quantify carotid plaque burden (cPB) (the sum of right and left carotid plaque areas) and by computed tomography for coronary artery calcium (CAC). Follow-up carotid vascular ultrasound was performed on 732 participants a median of 8.9 years after the baseline exam. All participants were followed up for all-cause mortality, the primary outcome. Trend HRs are the per-tertile increase in each variable. Over a median 12.4 years' follow-up, 901 (16%) participants died. After adjustment for cardiovascular risk factors and background medication, baseline cPB and CAC score were both significantly associated with all-cause mortality (fully adjusted trend HR: 1.23; 95% CI: 1.16-1.32; and HR: 1.15; 95% CI: 1.08-1.23), respectively (both P < 0.001), thus providing additional prognostic value. cPB performed better than CAC score. In participants with a second vascular ultrasound evaluation, median cPB progressed from 29.2 to 91.3 mm³. cPB progression was significantly associated with all-cause mortality after adjusting for cardiovascular risk factors and baseline cPB (HR: 1.03; 95% CI: 1.01-1.04 per absolute 10-mm³ change; P = 0.01). Subclinical atherosclerosis burden (cPB and CAC) in asymptomatic individuals was independently associated with all-cause mortality. Moreover, atherosclerosis progression was independently associated with all-cause mortality.

Experimental studies suggest that increased bone marrow (BM) activity is involved in the association between cardiovascular risk factors and inflammation in atherosclerosis. However, human data to support this association are sparse. The purpose was to study the association between cardiovascular risk factors, BM activation, and subclinical atherosclerosis. Whole body vascular ¹⁸F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (¹⁸F-FDG PET/MRI) was performed in 745 apparently healthy individuals [median age 50.5 (46.8–53.6) years, 83.8% men] from the Progression of Early Subclinical Atherosclerosis (PESA) study. Bone marrow activation (defined as BM ¹⁸F-FDG uptake above the median maximal standardized uptake value) was assessed in the lumbar vertebrae (L3–L4). Systemic inflammation was indexed from circulating biomarkers. Early atherosclerosis was evaluated by arterial metabolic activity by ¹⁸F-FDG uptake in five vascular territories. Late atherosclerosis was evaluated by fully formed plaques on MRI. Subjects with BM activation were more frequently men (87.6 vs. 80.0%, P = 0.005) and more frequently had metabolic syndrome (MetS) (22.2 vs. 6.7%, P < 0.001). Bone marrow activation was significantly associated with all MetS components. Bone marrow activation was also associated with increased haematopoiesis—characterized by significantly elevated leucocyte (mainly neutrophil and monocytes) and erythrocyte counts—and with markers of systemic inflammation including high-sensitivity C-reactive protein, ferritin, fibrinogen, P-selectin, and vascular cell adhesion molecule-1. The associations between BM activation and MetS (and its components) and increased erythropoiesis were maintained in the subgroup of participants with no systemic inflammation. Bone marrow activation was significantly associated with high arterial metabolic activity (¹⁸F-FDG uptake). The co-occurrence of BM activation and arterial ¹⁸F-FDG uptake was associated with more advanced atherosclerosis (i.e. plaque presence and burden). In apparently healthy individuals, BM ¹⁸F-FDG uptake is associated with MetS and its components, even in the absence of systemic inflammation, and with elevated counts of circulating leucocytes. Bone marrow activation is associated with early atherosclerosis, characterized by high arterial metabolic activity. Bone marrow activation appears to be an early phenomenon in atherosclerosis development. [Progression of Early Subclinical Atherosclerosis (PESA); NCT01410318]. The hypothesis of the natural history of the inflammatory process involving the atherosclerotic plaque formation. Bone marrow (BM) is implicated in the atherosclerotic process long before the appearance of acute cardiovascular events. Cardiovascular risk factors trigger BM activation, initially in the absence of systemic inflammation. As BM activation progresses, it is accompanied by an increase in haematopoietic progenitor cells and an associated increase in inflammatory markers. The next step in the process is arterial inflammation, leading to an increase in atherosclerotic burden.

Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure. Obesity is a modifiable risk factor of HFpEF; however, body mass index provides limited information on visceral adiposity and patients with similar anthropometrics can present variable cardiovascular risk. Epicardial adipose tissue (EAT) is the closest fat deposit to the heart and has been proposed as a biomarker of visceral adiposity. EAT may be particularly important for cardiac function, because of its location (under the pericardium) and because it acts as a metabolically active endocrine organ (which can produce both beneficial and detrimental cytokines). In this paper, the authors review the role of EAT in normal and pathologic conditions and discuss the noninvasive imaging modalities that allow its identification. This review highlights EAT implications in HFpEF and discuss new therapies that act on EAT and might also exert beneficial effects on the cardiovascular system.

Aims As evidenced by scintigraphy imaging, the prevalence of transthyretin (TTR) cardiac amyloidosis in heart failure patients with preserved ejection fraction (HFpEF) and left ventricular hypertrophy (LVH) ranges between 13% and 19%. The natural evolution of cardiac amyloidosis begins with the deposition of amyloid material in the myocardium, with LVH ensuing at later stages. With current imaging modalities, it is possible to detect TTR cardiac amyloidosis before the hypertrophic stage. The aim of this study was to determine the prevalence of TTR cardiac amyloidosis in HFpEF patients without LVH. Methods and results The study prospectively enrolled patients admitted for HF with LV ejection fraction (LVEF) ≥ 50% and LV wall thickness <12 mm. TTR cardiac amyloidosis was diagnosed according to accepted criteria, which include positive cardiac 99‐Tc‐DPD scintigraphy in the absence of monoclonal protein expansion in blood. Transthyretin gene sequencing was performed in positive patients. From July 2017 to January 2020, 329 patients with HFpEF and LV thickness <12 mm were identified. After exclusions, 58 patients completed the study with cardiac scintigraphy (79 years, 54% men; median LVEF 60% and LV wall thickness 10.5 mm). Three patients (5.2%) were positive for TTR cardiac amyloidosis; genetic analysis excluded the presence of hereditary TTR amyloidosis. Positive patients baseline characteristics (84 years, 67% men, LVEF 60%, and LV wall thickness 11 mm) were similar to patients without TTR, except for troponin levels (0.05 vs. 0.02 ng/mL, P = 0.03) and glomerular filtration rate (82 vs. 60 mL/min, P = 0.032), which were higher in TTR patients. Conclusions In a cohort of patients with HFpEF without LVH, the prevalence of TTR cardiac amyloidosis was 5%. Early diagnosis of cardiac involvement in TTR amyloidosis (before manifest LVH) would seem recommendable because newly approved specific treatments can prevent additional deposition of amyloid material.