Sequential nephron blockade with combined diuretics improves diastolic function in patients with resistant hypertension

AIMS: Hypertension is a major contributor to cardiac diastolic dysfunction. Different therapeutics strategies have been proposed to control blood pressure (BP), but their independent impact on cardiac function remains undetermined. In patients with resistant hypertension, we compared the changes in cardiac parameters between two strategies based on sequential nephron blockade (NBD) with a combination of diuretics or sequential renin‐angiotensin system blockade (RASB). METHODS AND RESULTS: After a 4‐week period where all patients received Irbesartan 300 mg/day + hydrochlorothiazide 12.5 mg/day + amlodipine 5 mg/day, 140 resistant hypertension patients (54.8 ± 11.1 years, 76% men, mean duration with hypertension: 13.1 ± 10.5 years, no previous history of heart failure or current symptoms of congestive heart failure) were randomized 1:1 to the NBD regimen or to the RASB regimen at week 0 (W0, baseline). Treatment intensity was increased at week 4, 8, or 10 if home BP was ≥135/85 mmHg, by sequentially adding 25 mg spironolactone, 20–40 mg furosemide, and 5 mg amiloride (NBD group) or 5–10 mg ramipril and 5–10 mg bisoprolol (RASB group). No other antihypertensive drug was allowed during the study. BP, BNP levels, and echocardiographic parameters were assessed at weeks 0 and 12. The baseline characteristics, laboratory parameters, and plasma hormones (BNP, renin, and aldosterone) and cardiac echocardiographic parameters did not significantly differ between the NBD and the RASB groups. Over 12 weeks, BNP levels significantly decreased in NBD but increased in RASB (mean [CI 95%] change in log‐transformed BNP levels: −43% [−67%; −23%] vs. +55% [46%; 62%] in NBD vs. RASB, respectively, P < 0.0001). Similarly, the proportion of patients presenting ≥2 echocardiographic criteria of diastolic dysfunction decreased between baseline and W12 from 31% to 3% in NBD but increased from 19% to 32% in RASB (P = 0.0048). As compared with RASB, NBD induced greater decrease in ambulatory systolic BP (P < 0.0001), pulse pressure (P < 0.0001), and systemic vascular resistance (P < 0.005). In multivariable linear regression analyses, NBD treatment was significantly associated with decreased BNP levels (adjusted ß: −46.41 ± 6.99, P < 0.0001) independent of age, gender, renal function, and changes in BPs or heart rate. CONCLUSIONS: In patients with resistant hypertension, nephron blockade with a combination of diuretics significantly improves cardiac markers of diastolic dysfunction independently of BP lowering.