We report a case of an elderly Caucasian male with past medical history of dextrocardia with situs inversus totalis, polymyalgia rheumatica, history of cryptogenic stroke, and severe mitral regurgitation with mitral valve prolapse, who presented with acute heart failure symptoms, including severe dyspnea on exertion and worsening lower extremity edema in the setting of immunosuppression with steroids for a year-old diagnosis of polymyalgia rheumatica. One month prior to this presentation, the patient suffered a transient ischemic attack and during the workup, his transthoracic echocardiography showed myxomatous degeneration of posterior mitral leaflet, partially flail, with severe mitral regurgitation, which required mitral valve replacement. Genome sequencing of mitral valve anterior leaflet pathology detected Tropheryma whipplei as a causal agent of culture-negative endocarditis. The patient was treated with 6 weeks of ceftriaxone and ampicillin-sulbactam and further continued trimethoprim-sulfamethoxazole for 1 year. He continued antibiotic treatment with resolution of shortness of breath along with arthralgia.