Abstract Background Mitral valve prolapse (MVP) reflects a connective tissue abnormality of the mitral leaflets leading to myxomatous degeneration. Early echocardiography and semeiotic assessment investigations suggested that connective tissue abnormalities might be extended to heart chambers, great vessels, and the skeletal system. Cardiac Magnetic Resonance (CMR) has unique potentials in evaluating MVP, cardiac chambers, aortic dimensions, and Haller Index, an expression of the deformity of the thoracic cage, at one time. Purpose We aimed to investigate the potential phenotypic systemic expressions of connective tissue disease in patients with MVP by CMR assessment. Methods This case-control study included consecutive patients with MVP and a control group of healthy volunteers undergoing CMR at our Institution from September 2020 to November 2023. Patients with more than mild mitral or aortic regurgitation, bicuspid aortic valve, or known systemic connective diseases were excluded. The MVP, cardiac chambers, aortic dimensions, and Haller Index were assessed according to standard practice. Results 103 patients with MVP and 57 healthy volunteers (51± 17 vs. 47±18 years, p=0.2, and 5% females vs. 54.4% females, p=0.8, respectively) were enrolled. Patients with MVP showed greater left ventricular end-diastolic (91±25 vs. 78±17 ml/m2; p=0.005) and end-systolic volumes (36±12 vs. 27±6; ml/m2; p<0.001), aortic annulus (13±2 vs. 12±2 mm/m2; p<0.001), sino-tubular junction (15±3 vs. 14±3 mm/m2; p=0.03), aortic root (19±3 vs. 17±3 mm/m2; p<0.001), and descending aorta (13±2 vs. 12±2 mm/m2; p=0.03), and higher Haller Index (2.8±0.6 vs. 2.6±0.4; p=0.02) than healthy controls. No differences were found in ascending aorta (18±3 vs. 17±3 mm/m2; p=0.3), pulmonary trunk (13±2 vs. 13±2 mm/m2; p=0.5), left atrial volume (38±18 vs. 30±15 ml/m2; p=0.20), right ventricular end-diastolic-volume (86±20 vs. 81±20 ml/m2; p=0.3) were found. At ANCOVA, sex and MVP affected the Haller Index values (p = 0.005 and 0.04). The association between MVP and Haller Index persisted after controlling for sex, age, and body surface area. In multivariate regression analysis, MVP and sex had an independent impact on ventricular and aortic dimensions, with MVP and male patients showing greater values. In particular, MVP was associated with an increase in the aortic annulus (Coefficient=1.2; p< 0.001), aortic root (Coefficient=1.5, p=0.001), descending aorta (Coefficient=0.7, p = 0.026), left ventricular end-diastolic-volume (Coefficient=11.1, p=0.01) and mass (Coefficient=5.7, p=0.02) after controlling for sex, age, and body surface area. Conclusions This pivotal study assessing systemic connective tissue disorders by CMR suggests abnormalities in the aorta and the skeletal system of patients with MVP, paving the way to larger investigations exploring the clinical impact of these findings.CMR findings in the study populationBox plots showing variables distribution