Connective tissue disorders and autoimmune diseases are special groups associated with heart disease. Connective tissue disorders like Marfan syndrome and Ehlers-Danlos syndrome affect collagen and the elasticity of joints. They can lead to dangerous complications when internal structures are affected, including aortic root dilatation/rupture and mitral valve prolapse. Dysautonomia is a relatively common comorbid condition in this population and includes conditions like postural tachycardia syndrome (POTS). Autoimmune diseases like systemic lupus erythematosus and rheumatoid arthritis affect the heart by increasing atherosclerosis, myocardial fibrosis, and vasculitis. These disorders may result in arrhythmias, heart failure, or valve dysfunction and require a multidisciplinary team of physicians to manage them properly.