Dose-finding of a novel natriuretic peptide-derived drug in a model of diastolic dysfunction
Heart failure (HF) is a complex disease characterized by the inability of the heart to pump an adequate amount of blood to meet the body's needs. HF is a major clinical challenge and is associated with a markedly increased risk of death. HF affects over 23 million people worldwide and accounts for the majority of hospitalizations among the elderly. Recently, it has been estimated that half of the patients with HF have diastolic dysfunction, which consists of an impaired relaxation of the heart while the fraction of blood pumped from the left ventricle into the circulation retains normal values.This condition is called HF with preserved ejection fraction (HFpEF). Overt HFpEF is often the final result of a slow progression of maladaptive cardiac remodeling events in conjunction with risk factors such as hypertension, diabetes, and obesity. Patients with HF are progressively getting worse by the concomitant presence of renal dysfunction, and vice versa. Currently, there is no treatment for HFpEF and there is a considerable necessity for new therapeutic approaches and strategies.
We propose a study where we administer a naturally produced cardiac hormone with unique cardiac, renal, and systemic protective actions. Our goal is to define the right dose at which this drug shows beneficial effects in a rat model of diastolic dysfunction. Of note, this drug is currently showing beneficial effects in an on-going clinical study of patients with acute worsening of chronic HF with reduced ejection fraction, but it has not been tested before for the treatment of HFpEF. Our study will be the first aimed at investigating the effects of this hormone in
diastolic HF.
The animal model chosen develops hypertension and renal failure when fed diets with high salt content. Within 4-6 weeks, the model develops diastolic dysfunction and within 28 weeks HFpEF. Generally, animals do not show signs of distress,as the severity category of the procedures for drug delivery, urine collection and blood pressure measurement are classified as mild or moderate. Given the favorable biological properties of the drug and the promising beneficial effects that have been observed in other clinic settings (e.g HFrEF), we aim to assess the utility of this
novel drug as a potential therapeutic intervention in HFpEF. To do so, we will test different doses (low, medium,high) and determine the optimal concentration based on its genotypic and phonotypical responses. Ideally, all of the doses tested will benefit the rat conditions at different degrees.
Studying the effects of this novel drug in the treatment of HFpEF is possible only if animals are used. The number of rodents required for our experiments is 100. The calculated amount of rats is based on preliminary data on the rat's heart structure and function. These data ought to guide us on whether our observations on the remodeled heart are casually or statistically valid. The collected data and tissues will be then available to the entire institute (IEMR) to allow other researchers to investigate on this animal model without the necessity to use more animals.
We propose a study where we administer a naturally produced cardiac hormone with unique cardiac, renal, and systemic protective actions. Our goal is to define the right dose at which this drug shows beneficial effects in a rat model of diastolic dysfunction. Of note, this drug is currently showing beneficial effects in an on-going clinical study of patients with acute worsening of chronic HF with reduced ejection fraction, but it has not been tested before for the treatment of HFpEF. Our study will be the first aimed at investigating the effects of this hormone in
diastolic HF.
The animal model chosen develops hypertension and renal failure when fed diets with high salt content. Within 4-6 weeks, the model develops diastolic dysfunction and within 28 weeks HFpEF. Generally, animals do not show signs of distress,as the severity category of the procedures for drug delivery, urine collection and blood pressure measurement are classified as mild or moderate. Given the favorable biological properties of the drug and the promising beneficial effects that have been observed in other clinic settings (e.g HFrEF), we aim to assess the utility of this
novel drug as a potential therapeutic intervention in HFpEF. To do so, we will test different doses (low, medium,high) and determine the optimal concentration based on its genotypic and phonotypical responses. Ideally, all of the doses tested will benefit the rat conditions at different degrees.
Studying the effects of this novel drug in the treatment of HFpEF is possible only if animals are used. The number of rodents required for our experiments is 100. The calculated amount of rats is based on preliminary data on the rat's heart structure and function. These data ought to guide us on whether our observations on the remodeled heart are casually or statistically valid. The collected data and tissues will be then available to the entire institute (IEMR) to allow other researchers to investigate on this animal model without the necessity to use more animals.