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We hypothesized that relief of obstruction in patients with hypertrophic cardiomyopathy (HC) by percutaneous transluminal septal myocardial ablation (PTSMA) improves microvascular dysfunction by relief of extravascular compression. Microvascular dysfunction in obstructive HC is related to extravascular compression by increased left ventricular (LV) mass and LV end-diastolic pressure. The study included 14 patients with obstructive HC (mean age 55+/-12 years, 11 men) who underwent successful PTSMA and 14 healthy volunteers (mean age 31+/-4 years, 11 men). LV hemodynamics (by Doppler echocardiography) and intramyocardial flow dynamics (by adenosine myocardial contrast echocardiography) were evaluated in healthy volunteers and before and 6 months after PTSMA in patients with HC. LV end-diastolic pressure was estimated from the ratio of transmitral early LV filling velocity to early diastolic mitral annular velocity. PTSMA reduced the invasively measured LV outflow tract gradient (119+/-35 vs 17+/-16 mm Hg, p<0.0001) and LV end-diastolic pressure (23+/-3 vs 16+/-2 mm Hg, p<0.001). Six months after PTSMA, myocardial flow reserve improved (2.73+/-0.56 vs 3.21+/-0.49, p<0.001), but did not normalize compared with healthy controls (vs 3.95+/-0.77, p<0.001). Also, septal hyperemic endo-to-epi myocardial blood flow ratio improved (0.70+/-0.11 vs 0.92+/-0.07, p<0.001). Changes in LV end-diastolic pressure, LV mass index, and LV outflow tract peak systolic gradient correlated well with changes in hyperemic perfusion (all p<0.05). In conclusion, microvascular dysfunction improves after PTSMA due to relief of extravascular compression forces.