Effects of Fixed-Dose Isosorbide Dinitrate/Hydralazine on Diastolic Function and Exercise Capacity in Hypertension-Induced Diastolic Heart Failure

Abstract

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 (nϭ18) or aldosterone (nϭ28) 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 (161Ϯ3 mm Hg) versus saline-infused mice (129Ϯ2 mm Hg). Aldosterone induced LV hypertrophy versus saline-infused mice (LV:body weight ratio: 4.2Ϯ0.1 versus 3.6Ϯ0.1 mg/g). HISDN attenuated the aldosterone-induced increased in systolic blood pressure (137Ϯ5 mm Hg) and also lowered blood pressure in saline-infused mice (114Ϯ2 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. Key Words: diastolic heart failure Ⅲ hydralazine Ⅲ nitrates Ⅲ hypertension Ⅲ exercise capacity H ypertension induces left ventricular (LV) hypertrophy (LVH) and is a major cause of both diastolic and systolic heart failures (HF). 1 Diastolic HF accounts for up to Յ50% of all HF presentations 2 and is associated with increasing morbidity and mortality. 3 Diastolic HF refers to the clinical syndrome of pulmonary congestion in the presence of a normal LV ejection fraction, whereas diastolic dysfunction denotes an abnormality of mechanical properties that exist during LV relaxation and filling. 4,5 Diastolic dysfunction may be an intermediary between hypertension and HF. 6 In the setting of hypertension, diastolic HF represents a diverse clinical syndrome with various associated comorbidities (eg, age and sex) and manifests a spectrum of symptoms ranging from exercise intolerance to acute pulmonary edema. In addition to LVH, cardiac...

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Effects of Adiponectin on Calcium-Handling Proteins in Heart Failure With Preserved Ejection Fraction

“…Heart rate and blood pressure (BP) were measured weekly using a noninvasive tail-cuff BP analyzer, BP-2000 Blood Pressure Analysis System (Visitech Systems, Inc., Apex, NC) 18, 20 .…”

“…Transthoracic echocardiography was performed at the end of 4 weeks using the Vevo 770 High-Resolution In Vivo Micro-Imaging System and a Real-Time Micro Visualization 707B Scanhead (VisualSonic Inc., Toronto, Ontario, Canada) 18, 20 . For details of LV structure, function and Doppler measurements see online supplement.…”

Myocardial Ischemia in Patients with Diastolic Dysfunction and Heart Failure

“…Nitric oxide donors have distensibility-increasing and relaxation-hastening effects in experimental animal models. Treating with fixed-dose hydralazine and isosorbide dinitrate in a mouse model of DHF demonstrated improved hypertension, diastolic function, and exercise capacity; however, it did not prevent progression of disease or alter cardiac fibrosis [39]. The effect of this agent in humans with DHF has not been addressed.…”

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