The impairment of adaptive mechanisms during orthostatic challenge may evoke orthostatic intolerance, a heterogeneous condition, in which the standing position elicits a fall in blood pressure and/or excessive tachycardia, accompanied by a wide spectrum of subjective symptoms such as dizziness, discomfort, nausea, and palpitations. Apart from chronic and potentially debilitating symptoms, orthostatic intolerance may occasionally lead to sudden loss of consciousness and fall injuries. Consequently, orthostatic intolerance should be considered as a possible cause of unexplained syncope. Two main forms of orthostatic intolerance are orthostatic hypotension (OH) and postural orthostatic tachycardia syndrome (POTS). Clinical variants of OH include initial, classical, and delayed forms. The prevalence of OH increases with age, ranging from less than 5% under 40 years to about 20% above 70 years of age, and is higher in chronic diseases, such as hypertension and diabetes, reaching above 35% in Parkinson’s disease and advanced kidney failure. The presence of OH is associated with a higher mortality and an increased incidence of cardiovascular disease, with the majority of patients being asymptomatic in normal conditions. In contrast, POTS affects predominantly young women (70–80%) within an age range of 15–40 years and is usually accompanied by non-specific symptoms: deconditioning, headache, cognitive impairment, and gastrointestinal dysfunction. Management of orthostatic intolerance includes both non-pharmacological and pharmacological methods with limited efficacy in the severe cases. Empirical treatment with vasoactive and volume expanding drugs for OH and POTS, and rhythm controlling therapy for POTS are recommended. Future studies on syndromes of orthostatic intolerance should focus on mechanisms leading to OH and POTS, novel diagnostic methods, and more effective therapeutic options.

Background Orthostatic hypotension in patients with a low ejection fraction has been associated with a very high morbidity and mortality. Some of this is due to co-morbidity and some is due to the inability to use conventional medications such as ACE inhibitors, ARBs, sacubitril/valsartan and beta blockers because of worsening hypotension. Midodrine and Florinef can raise blood pressure, but are limited in their ability to do so and have theoretical disadvantages due to increase in systemic resistance and increase in volume overload, respectively. Droxidopa, a new treatment for orthostatic hypotension due to autonomic failure, is metabolized into norepinephrine and could potentially provide a new treatment modality for these very difficult patients. Case report We treated a 71 -year-old, Caucasian male with chronic atrial fibrillation and non-ischemic cardiomyopathy. Even with a biventricular defibrillator, severe orthostatic hypotension continued resulting in falls and head trauma. He was unable to tolerate any of the conventional medications to try to raise his ejection fraction due to worsening hypotension. Droxidopa was initiated and progressively up titrated, finally reaching a dose of 300 mg t.i.d. At this dose, his blood pressure stabilized and he was able to tolerate the following medications: Sacubitril/valsartan 24/26 b.i.d., metoprolol succinate 25 mg daily. On this medicine combination his blood pressure ranged from 101/58 to 110/65 and his New York Heart Association class improved from class IV to class II. LV ejection fraction was 30% initially and increased to 50% after 4 months of treatment with Droxidopa. He became ambulatory and had a much improved quality of life. Renal function and other laboratory parameters remained stable on the droxidopa. His ICD interrogation showed no evidence of any proarrhythmia affects of droxidopa. Conclusion Droxidopa provides potentially a new treatment modality for patients with low ejection fraction and refractory orthostatic hypotension. Longer term follow up will be needed to confirm efficacy and safety. Rhythm follow up of over 9 months has shown no evidence of proarrhythmia. Additional patients and longer term follow up results are in preparation, but have had similar benefits to date.

Orthostatic hypotension occurs when there is an abnormal or delayed response to shifts in the body's fluid balance upon standing, resulting in an exaggerated drop in SBP (≥20 mm Hg) or diastolic blood pressure (≥10 mm Hg). Responses can be of several types, as mentioned below. "Classic" orthostatic hypotension occurs within 3 minutes of standing. "Delayed" orthostatic hypotension occurs after 3 minutes. "Initial" orthostatic hypotension lasts less than 15 seconds after postural changes. "Delayed blood pressure recovery" refers to a blood pressure drop that returns to its original values at a time longer than 15 seconds. Most studies have focused on classic orthostatic hypotension, with limited data available on other types. [13]  Over 95% of patients can be diagnosed based on systolic hypotension alone, making it the most commonly reported metric for this condition. [14]  In addition, orthostatic hypotension can also be classified based on the timing of SBP decrease and recovery. Recurrent and transient symptoms are characteristic of initial orthostatic hypotension, whereas classic orthostatic hypotension typically presents with more prolonged symptoms, such as blurred vision, light-headedness, or syncope, occurring over a period of up to 180 seconds. [10] [15] Epidemiology The prevalence of orthostatic hypotension increases with age, particularly in individuals aged 65 or older, due to impaired baroreceptor sensitivity. A systematic review and meta-analysis found that 1 in 5 adults aged 60 or older living in the community experience orthostatic hypotension, with rates being even higher among those residing in long-term care facilities. [16]  Two large population-based studies conducted in the United States suggest that orthostatic hypotension is present in less than 5% of individuals aged 45 to 49, approximately 15% of those aged 65 to 69, and over 25% of individuals aged 85 and