Abstract Background Infective endocarditis (IE) is a rare yet serious condition affecting the heart valves and the endocardium. Despite advances in management, IE's incidence is on the rise, maintaining a mortality rate similar to that of the late 20th century. Notably, there has been a notable shift in the risk-factor profile, transitioning from traditional factors such as rheumatic heart disease and poor dental health to more iatrogenic causes such as prosthetic heart valves, cardiac devices, foreign body implants, haemodialysis, and immunosuppression. This shift impacts microbiological and imaging diagnosis. Purpose While IE has been extensively studied in the past, the evolving landscape prompts an epidemiological re-evaluation of vulnerable patient populations and the challenges in current diagnostic parameters. Our primary objective is to examine the trends in microbiological and imaging diagnostics over two decades and to compare them across native valve endocarditis (NVE), prosthetic valve endocarditis (PVE), and cardiac implantable electronic device-related IE (CIED-IE). Methods We conducted a retrospective analysis of longitudinal data encompassing 912 patients admitted with either a possible or definite IE diagnosis between 2001 and 2023. Results The incidence of IE increased over the study duration (p<0.01) with octogenarians most affected (21%). Iatrogenic risk factors were associated with nearly two-thirds (63%) of patients diagnosed with IE, while traditional risk factors were evident in almost one-eighth (13%). Blood culture-negative endocarditis increased over the study duration (81% versus73%, p<0.01) and Staphylococcus aureus (29%, p<0.01) became the dominant pathogen over Viridans Streptococcus (14%, p=0.001). Imaging with transthoracic (56% in 2004 versus 75% in 2023) and transoesophageal echocardiography (57% in 2004 versus 79% in 2023) had an increasing contribution in the diagnosis of IE over the two decades. The subgroup analysis found PVE and CIED-IE were more likely to have negative blood cultures (OR=3.7, CI [1.2-6.8] & OR=4.9, CI [1.3-8]) compared to NVE (OR=0.04, CI [0.02-0.8]). PVE and CIED-IE were more likely to have inconclusive imaging (OR=3.7, CI [1.2-6.6] & OR=2.2, CI [0.07-7.8]) compared to NVE (OR=0.63, CI [0.3-3.2]). Complications of stroke were higher in PVE (OR=3.5, CI [0.89-10]) compared to NVE which also had a lower stroke rate (OR=.16, CI [.04-.73]). PVE had more valvular insufficiency (OR=2.1, CI [0.6-4]) compared to NVE (OR=1.2, CI [0.9-6]). The 12-month mortality was no different across the entities (OR=0.3, CI [0.5-7.7] & OR=.49, CI [0.14-1.8] & OR=0.85, CI [0.3-2.4]). Conclusion Our study underscores the evolving nature of IE, now predominantly a healthcare-related disease. Diagnostic challenges persist due to the heterogeneity of the disease, with the emergence of distinct entities such as PVE and CIED-IE.Graphs: Blood culture & echocardiographyForest plot: NVE vs PVE vs CIED-IE
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