Heart failure (HF) is the most common hospitalized cardiovascular outcome among subjects with chronic kidney disease (CKD). A series of animal and human studies strongly suggest that arterial wave reflections (which increase the late systolic workload of the left ventricle) lead to the development of left ventricular (LV) remodelin, fibrosis, dysfunction and the risk of heart failure. The strong association between wave reflections and LV failure suggests that wave reflections are a suitable therapeutic target, but a randomized trial that targets wave reflections to improve cardiac hypertrophy, fibrosis and dysfunction (known precursors to heart failure) has never been performed. Therefore, we lack the proof of concept of causality in humans. Such proof of concept would establish a new therapeutic paradigm too. Subjects with CKD demonstrate prominent wave reflections. We propose a double-blind, parallel-arm randomized placebo-controlled trial enrolling 130 patients with CKD, in order to test the hypothesis that 24 weeks of isosorbide mononitrate therapy (ISMN), which blunts wave reflections, will improve LV hypertrophy (a precursor to heart failure) and other important cardiac quantitative endpoints. (1) PRIMARY AIM: To test whether therapy with ISMN for 24 weeks reduces LV hypertrophy (i.e., LV mass, measured with steady-state free precession MRI), diffuse cardiac fibrosis (measured via novel myocardial T1 mapping MRI techniques), myocardial systolic function (i.e, myocardial systolic strain measured with MRI) and diastolic function (mitral annular tissue Doppler diastolic velocity). (2) SECONDARY AIMS: SECONDARY AIM 1: To establish that the mediator for improvement in cardiac endpoints in response to ISMN therapy is the reduction in wave reflections, rather than a simple reduction in brachial blood pressure (BP). This will be achieved by minimizing variability in brachial blood pressure between the groups with a per-protocol BP goal in all randomized subjects; (2) Applying ad hoc causal modeling. SECONDARY AIM 2: As an exploratory aim, we will apply an unbiased biomarker discovery approach to identify biomarkers/pathways that either (a) are present at baseline and predict the degree of response to SR-ISMN therapy; (b) Demonstrate characteristics of a mediator of the effect of randomized therapy on the cardiac endpoints. We will apply a novel proteomic approach (SOMAscan) to measure levels of 1129 candidate biomarkers at baseline and after randomized therapy. If our intervention improves LV remodeling, myocardial function and renal endpoints, this would establish a new therapeutic paradigm and would provide the foundation for justifying, designing and powering a definitive hard endpoint-driven clinical trial for primary HF prevention and/or CKD progression in patients with CKD using this inexpensive, readily available intervention.
Heart failure (HF) is the most common hospitalized cardiovascular outcome in chronic kidney disease (CKD). Arterial wave reflections, which are increased in CKD, increase the late systolic load of the left ventricle (LV), promoting LV hypertrophy/dysfunction in animals. The malignant nature of late systolic load is supported only by observational data in humans. This double- blind, randomized-controlled trial will enroll 130 CKD patients, to test the hypothesis that isosorbide mononitrate (which reduces late systolic load), will improve LV hypertrophy, fibrosis and dysfunction. This would represent the first proof of concept that reducing late systolic load leads to improvements in cardiac remodeling/function.
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