Brian D. Lowes, Ph.D. - US grants

This is a multicenter, double blind, randomized, placebo-controlled study of the onset and offset of hemodynamic effects and plasma drug concentrations following sustained infusions of opc-18790 in patients with nyha class III-IV heart failure. Opc-18790 is a phosphodiesterase inhibitor with direct inotropic effects. Unlike other inotropes, opc-18790 also possesses mild vasodilatory activity resulting in after load reduction. Inotrophy and vasodilatation, combined with opc's effect on sinus node automaticity, make his compound a promising new therapy for the treatment of advanced heart failure.

This is a multicenter, randomized, double-blind trial to evaluate the hemodynamic effects, safety and tolerability of bms-186716 after a single oral dose and after 12 weeks of once-daily oral therapy in subjects with heart failure (nyha class II-IV and resting lvef, /- 40%). Bms-186716 is a novel dual-metalloprotease inhibitor providing selective inhibition of neutral endopeptidase (nep) and angiotensin converting enzyme (ac). Inhibition of nep and ace prevents the enzymatic degradation of atrial natriuretic peptide and brain natriuretic peptide thereby potentiating the intrinsic diuretic, natriuretic, vasodilatory and anti-proliferative actions of these endogenous vasoactive proteins. Nep and ace also play a role in the hydrolysis of bradykinins resulting in vasodilation, increased renal blood flow and improved natriuresis. This dual inhibition is postulated to therefore improve the hemodynamic functioning of the failing heart through pre and after-load reduction leading to improvements in functional status in subjects with heart failure.

Endothelins (ET) are a family of vasoactive peptides. Since their discovery in 1988, ET have been investigated for their physiological function and potential pathological role in cardiovascular disease. Three members of the family, ET-1, ET-2 and ET-3, are produced in a variety of tissues including vascular endothelium, vascular smooth muscle, and myocardium, where they act via endocrine and paracrine pathways to modulate vasomotor tone, cell proliferation, and the renin-angiotensin-aldosterone system. ET-1 is a biologically active 21 amino acid peptide that is cleaved by endothelin converting enzyme from "big" ET-1, a 38 amino acid peptide possessing 1/100 the biologic activity of the mature ET. ET-1 binds to two types of endothelin receptors, ETA and ETB. ETA receptors have the greatest affinity for ET-1 and are expressed predominately in vascular smooth muscle cells, where their activation mediates vasoconstriction. ETB receptors are found on endothelial cells and, to a much lesser extent on vascular smooth muscle cells. Stimulation of smooth muscle cell ETB receptors leads to the release of endothelium-dependent vasodilators, nitric oxide and prostacyclin. Pulmonary ETB receptors have been implicated in the clearance of ET from plasma. The myocardium expresses both ETA and ETB receptors, although ETA receptors predominate and their activation by exogenously applied ET produces a positive inotropic response. Patients with more severe heart failure have elevated plasma ET levels. The magnitude of the elevated levels is positively correlated with NYHA Functional Class and left ventricular and diastolic volume. It is inversely related to left ventricular ejection fraction, cardiac index, and survival (in advanced heart failure). Plasma ET levels measured during exercise also appear to be inversely related to exercise capacity. Patients with the highest ET-1 levels at the time of maximal exercise achieved the lowest levels of maximum oxygen consumption. Blocking the effects of ET has the potential to ameliorate the clinical signs and symptoms of heart failure. Based on its preclinical profile, the ETA selective receptor antagonist BMS-193884 is expected to be an effective therapeutic intervention in patients with heart failure. To define a therapeutic dose range, this initial phase II study will evaluate the hemodynamic effects of several single, oral doses of BMS-193884 in patients receiving conventional, concomitant therapy, including ACE1.

thyroid hormones; human therapy evaluation; heart failure; gene expression; hormone therapy; hormone regulation /control mechanism; clinical research; human subject;

DESCRIPTION (provided by the applicant): The mechanisms responsible for progressive myocardial dysfunction and remodeling of the cardiomyopathic, intact failing human heart are unknown. The mechanism(s) behind Beta-blocker related improvements in myocardial function and reversal of remodeling also remains unknown. In general, the pathophysiologic mechanisms responsible for progressive myocardial failure and remodeling are likely to involve signaling mechanisms, which alter myocardial gene expression. Similarly, the molecular basis for improvement in myocardial function and remodeling following treatment with Beta-blocking agents also is likely due to time-dependent changes in myocardial gene expression. Numerous recent studies have demonstrated that, in order to be meaningful, gene regulation and expression must be examined in the intact heart. The overall objective of this proposal is to identify, in human subjects with myocardial failure, gene expression profiles associated with changes in myocardial function. This proposal investigates 1) the expression of over 12,000 genes in the failing human heart relative to nonfailing controls 2)changes in gene expression associated with Beta-blocker related improvement in myocardial function. Using microarray analysis we are able to measure the expression of a large number of genes in small quantities of human ventricular myocardium that can be obtained serially from the intact heart by right ventricular (RV) endomyocardial biopsy. We have demonstrated that in situations where left and right ventricular function are concordant, directional changes in gene expression are similar in RV free wall, RV septal endomyocardium, and LV free wall, indicating that RV septal endomyocardial biopsy samples may be used to investigate changes in RV or LV free wall gene expression. Thus, this proposal has the ability to determine the molecular mechanisms responsible for myocyte dysfunction in the intact human heart. Furthermore, this proposal has the ability to provide information relevant to the mechanisms responsible for Beta-blocker-related improvements in myocardial dysfunction.

thyroid hormones; human therapy evaluation; heart failure; hormone therapy; hormone regulation /control mechanism; gene expression; genetic regulation; beta adrenergic receptor; myosins; heart function; patient oriented research; clinical research; human subject;

DESCRIPTION (provided by applicant): Congestive heart failure is an enormously prevalent disease in Western society and is associated with substantial morbidity and mortality as well as with staggering health care costs. It is difficult to predict which patients will and will not respond to therapy. The subset of patients who don't respond to pharmacotherapy truly benefit from device therapy and/or consideration of mechanical support and/or transplant but often receive these interventions too late, after their disease has progressed or they have developed a morbid complication. Ejection fraction, functional capacity and multivariate heart failure "scores" have been utilized to guide clinical decisions, but have poor predictive values for disease progression. Our preliminary data, derived from the on-going BORG trial, suggest the general hypothesis that molecular profiling coupled with proteomic and genomic analyses of tissue obtained from an endomyocardial biopsy can offer a robust predictive tool that will allow for the early identification of patients who will and will not respond to pharmacotherapy. Therefore the broad goals of this C-TRIP proposal are first (Phase 1) to validate our methodology using this patient cohort that has already been clinically characterized and from whom serial endomyocardial biopsy material has already been collected and then subsequently (Phase 2) to design and execute a multicenter clinical trial that will use this methodology to prospectively predict heart failure progression. Our goal is to translate a molecular understanding of heart failure into clinical tools which can guide the diagnosis, classification, and management of these patients. Aim1 will develop a predictive algorithm from the analysis of an existing cohort of 72 patients with dilated cardiomyopathy who have undergone serial endomyocardial biopsies before and after initiation of betablocker therapy. This will be based on: A) mRNA profiling B) miRNA array data and C) quantitative proteomic assays targeting protein changes. Aim 2 will establish the infrastructure necessary to conduct a multi-center trial of patients with DCM in order to validate the predictive algorithm, with the goal of minimizing the health costs incurred by these patients and optimizing their care. RELEVANCE (See instructions): Our goal is to develop a personalized targeted approach to patient care incorporating molecular biomarkers from endomyocardial biopsies into a predictive model for heart failure patients. We believe patients identified early as non-responders should receive intervention targeted against preventing sudden cardiac death or death due to pump failure.