A multi-centre, randomized, double-blind, placebo-controlled phase II study to assess the effect of Serelaxin versus placebo on high-sensitivity cardia troponin I (hs-cTnl) release in patients with chronic heart failure after exercise when used in additio

Project Description

Numerous pathophysiological mechanisms are responsible for heart failure such as myocardial injury, oxidative stress, neuro-hormonal activation, inflammation, fibrosis and apoptosis. Besides B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP), multiple cardiac biomarkers are required to capture the full extent of the disease (Gaggin et al 2013). Among these biomarkers, cardiac troponin I (cTnI – inhibitory, 24kDa), and troponin T (cTnT–tropomyosin binding, 37 kDa) play an integral role (Torre and Jarolim 2015).

Cardiac troponins are elevated in patients with myocyte necrosis, prolonged ischemia, heart failure, myocarditis, sepsis and renal failure (McMurray et al 2012). However, low concentrations of cTnI and cTnT are also present in the plasma of healthy individuals, and their concentrations increase with age, cardiovascular disease and comorbidities, as well as in stress test-induced myocardial ischemia (Sabatine et al 2009).

The best described mechanism leading to raised cTns is myocardial ischemia in the setting of acute coronary syndromes or myocardial infarction (Hamm 1994). Possible mechanisms for the release of cTnT and cTnI in chronic heart failure (CHF) may include ventricular remodeling, presence of coronary artery disease, abnormalities of coronary microcirculation, and reduced coronary reserve (Del Carlo and O’Connor 1999). Other mechanisms leading to cTn elevation in heart failure remain elusive, but prominently include supply–demand inequity, endothelial dysfunction, increased oxygen demand related to increased wall tension, anemia, or other factors provoking subendocardial injury (Brett et al 1989).

Data suggest that cTn get released from 2 different pools in cardiomyocytes. More than 90% is bound to the myofibrillar apparatus, while a small percentage (6-8%) is found unbound in the cytosol. The free pool of cTns appears to be released relatively rapidly, i.e., within the first 1 to 2 hours following cardiac stress. In contrast, the myofibrillar-bound troponin pool is slowly and gradually released into the blood stream after cell necrosis, and cTns derived from this pool can be detected during a prolonged period, i.e., several days, after the acute injury (Omland et al 2015).The cellular events responsible for the release of the free pool of cTns in the setting of pure cardiomyocyte ischemia without necrosis remains controversial. Hessel et al (2008) showed the release of intact cTnI from viable cardiomyocytes in a model of reversible damage by stimulation of stretch-responsive integrins. Other studies showed the release of intact and fragmented cTns following irreversible cardiomyocyte damage
(Hessel et al 2008, Streng et al 2013).

Over the past several years, manufacturers of cTn assays have improved the quality specifications of assays to allow for more precise quantitation of low cTn concentrations (Apple et al 2007). The use of novel ultrasensitive assays has made it possible to measure low levels of cTns and to demonstrate that brief periods of stress-test induced myocardial ischemia are associated with quantifiable rises in the concentration of circulating troponin (Apple et al 2012). It has been show in a setting of stress test-induced myocardial ischemia, a model that is unlikely to cause irreversible cardiomyocyte damage, the possibility that transient provoked ischemia can produce troponin release in the absence of necrosis (Sabatine et al 2009).

Serelaxin, administered to acute heart failure (AHF) patients as a 48-hour i.v. infusion, in addition to standard of care (SoC) treatment, improved dyspnea and the incidence of in-hospital worsening heart failure among a range of other in-hospital clinical benefits. These clinical improvements were associated with significant improvements in biomarkers, with evidence of less end-organ damage in serelaxin-treated patients (Metra et al 2013). Serelaxin administration improved markers of cardiac (hs-cTnT), renal (creatinine and cystatin-C), and hepatic (aspartate transaminase and alanine transaminase) damage and of decongestion (NT-proBNP), consistent with the prevention of organ damage and faster decongestion (Metra et al 2013). Furthermore, the analysis of all-cause mortality through Day 180 showed a significant reduction of the number of deaths with serelaxin compared to placebo (Teerlink et al 2014).

The suggested effects of serelaxin may involve the protection of the cardiac myocyte from mechanical stress, oxygen supply-demand mismatch and troponin degradation via promotion of flow and vasodilation in the coronary arteries and prevention of troponin leakage. This could potentially lead to a reduction in troponin release after standard exercise test in patients with heart failure. This study aims at assessing whether the i.v. administration of serelaxin can prevent the cardiomyocyte from releasing cTns after a cardiac stress test providing additional evidence on the suggested cardioprotective properties of serelaxin in a model of rapid release of cTns.