title: Effects of fixed-dose isosorbide dinitrate/hydralazine on diastolic function and exercise capacity in hypertension-induced diastolic heart failure.
abstract: Hypertension-induced diastolic heart failure accounts for a large proportion of all heart failure presentations. Hypertension also induces left ventricular (LV) hypertrophy. Fixed-dose isosorbide dinitrate/hydralazine (HISDN) decreased mortality in human systolic heart failure but it is unknown whether it improves maladaptive myocardial remodeling. We sought to test the hypothesis that chronic HISDN modulates LV hypertrophy and myocardial remodeling in hypertension-induced diastolic heart failure. FVB mice underwent either saline (n=18) or aldosterone (n=28) infusion. All underwent uninephrectomy and drank 1% salt water for 4 weeks. Mice were randomized after surgery to regular chow or chow containing HISDN (isosorbide dinitrate: 26 mg/kg per day; hydralazine: 50 mg/kg per day) for 4 weeks. Aldosterone infusion increased tail-cuff blood pressure (161+/-3 mm Hg) versus saline-infused mice (129+/-2 mm Hg). Aldosterone induced LV hypertrophy versus saline-infused mice (LV:body weight ratio: 4.2+/-0.1 versus 3.6+/-0.1 mg/g). HISDN attenuated the aldosterone-induced increased in systolic blood pressure (137+/-5 mm Hg) and also lowered blood pressure in saline-infused mice (114+/-2 mm Hg). However, HISDN did not cause LV hypertrophy regression in aldosterone-infused mice. Aldosterone increased LV end-diastolic dimensions that were not attenuated by HISDN. Similarly, neither aldosterone infusion nor HISDN affected LV end-systolic dimensions. LV ejection fraction and wet:dry lung ratio were not different between aldosterone-untreated and aldosterone-HISDN mice. However, mitral Doppler E/A ratio (a measure of diastolic function), exercise capacity, and plasma soluble vascular cell adhesion molecule 1 levels were improved in aldosterone-HISDN hearts. In conclusion, fixed-dose HISDN improved hypertension, diastolic function, and exercise capacity and reduced soluble vascular cell adhesion molecule 1 levels. There were no reductions in LV hypertrophy, cardiac fibrosis, or pulmonary congestion. These functional improvements are likely related to extracardiac effects, such as effects on the vasculature.
authors.affiliation: Whitaker Cardiovascular Institute, Boston University School of Medicine, Evans Department of Medicine and Cardiovascular Section, 715 Albany Street, Boston, MA 02118, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Wilson
authors.forename: Deepa S
authors.initials: DS
authors.lastname: De Silva
authors.forename: Kaori
authors.initials: K
authors.lastname: Sato
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Izumiya
authors.forename: Flora
authors.initials: F
authors.lastname: Sam
mesh_terms: D000450:Aldosterone / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001794:Blood Pressure / Q000187:drug effects*; D016207:Cytokines / Q000235:genetics; D003971:Diastole; D004359:Drug Therapy, Combination; D015150:Echocardiography, Doppler; D005080:Exercise Test; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D006830:Hydralazine / Q000494:pharmacology* / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D007548:Isosorbide Dinitrate / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009206:Myocardium / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage / Q000633:toxicity; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D016207:Cytokines; D017673:Sodium Chloride, Dietary; D019010:Vascular Cell Adhesion Molecule-1; D014665:Vasodilator Agents; D006830:Hydralazine; D000450:Aldosterone; D009320:Atrial Natriuretic Factor; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; D007548:Isosorbide Dinitrate