Assessment of Novel Therapeutic Targets for Heart Failure: Insights from Preclinical Models

Fabrizio Laconi^*
*Correspondence: Fabrizio Laconi, Department of Cardiology, University of Toronto, 27 King’s College Cir, Toronto, ON M5S 1A1, Canada, Email:

Abstract

Heart failure remains a significant public health challenge with increasing prevalence worldwide. Despite advancements in treatment, mortality and morbidity rates remain high, highlighting the need for novel therapeutic approaches. Preclinical models play a crucial role in evaluating potential therapeutic targets for HF. This review provides insights into recent advancements in the assessment of novel therapeutic targets for HF using preclinical models, highlighting their translational potential and challenges in clinical translation.

Keywords

Heart failure • Cardiovascular complications • Hypertension

Introduction

Heart failure is a complex syndrome characterized by the inability of the heart to pump blood efficiently to meet the body's demands. Despite significant advancements in treatment, HF remains a leading cause of morbidity and mortality worldwide. Traditional therapies primarily target neurohormonal pathways, but their efficacy is limited, necessitating the exploration of novel therapeutic targets. Preclinical models, including animal models and in vitro studies, are essential tools for evaluating potential therapeutic targets for HF. These models allow researchers to study disease mechanisms, test the efficacy and safety of novel interventions, and optimize treatment strategies before clinical translation. Commonly used animal models include rodent models (e.g., mice and rats) and larger animal models (e.g., pigs and dogs), each with unique advantages and limitations.

Preclinical models help researchers understand the underlying mechanisms of HF, including cardiac remodeling, inflammation, oxidative stress, and mitochondrial dysfunction. By elucidating these mechanisms, researchers can identify novel therapeutic targets and develop targeted therapies. Novel therapeutic targets identified through basic research or clinical observations can be evaluated in preclinical models to assess their efficacy and safety. This includes pharmacological interventions targeting specific pathways or genetic manipulations to investigate the role of individual genes in HF development and progression.

Literature Review

Preclinical models allow researchers to optimize treatment strategies by testing different drug dosages, formulations, and delivery methods. This helps in identifying the most effective and least toxic treatment regimens before moving to clinical trials. Insights gained from preclinical studies can provide valuable predictive information about potential clinical outcomes of novel therapies in human patients [1-3]. Understanding how interventions affect cardiac function, remodeling, and survival in preclinical models can guide the design and interpretation of clinical trials.

Reduce Risks and Costs preclinical models, researchers can reduce the risks and costs associated with clinical trials. Early identification of ineffective or unsafe treatments can prevent their progression to human trials, saving time, resources, and patient exposure to unnecessary risks. Recent research has identified several promising therapeutic targets for HF, including molecular pathways involved in cardiac remodeling, inflammation, oxidative stress, and mitochondrial dysfunction. Examples include targeting the renin-angiotensin-aldosterone system, the β-adrenergic pathway, inflammatory cytokines, and microRNAs. Preclinical studies have provided valuable insights into the mechanisms of action and potential benefits of targeting these pathways.

Discussion

Various molecular pathways involved in cardiac remodeling, such as the renin-angiotensin-aldosterone system and the β-adrenergic pathway, are targeted for HF treatment. Novel therapies aim to modulate these pathways to prevent adverse remodeling and improve cardiac function. Inflammation plays a significant role in HF progression. Targeting inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1β with biologic agents or small molecule inhibitors has shown promise in preclinical studies for reducing inflammation and improving cardiac function [4,5].

Increased oxidative stress contributes to HF pathogenesis by causing cellular damage and impairing cardiac function. Antioxidant therapies targeting reactive oxygen species production or enhancing antioxidant defense mechanisms represent potential strategies for HF treatment. miRNAs regulate gene expression and have been implicated in various aspects of HF, including cardiac hypertrophy, fibrosis, and apoptosis. Modulating specific miRNAs with antisense oligonucleotides or miRNA mimics holds promise for regulating gene expression and attenuating HF progression. Abnormal calcium handling is a hallmark of HF. Targeting calcium-handling proteins, such as sarcoplasmic reticulum calcium ATPase and the sodium-calcium exchanger, aims to restore calcium homeostasis and improve cardiac contractility.

Impaired mitochondrial function contributes to HF pathophysiology. Therapies targeting mitochondrial biogenesis, oxidative phosphorylation, or mitochondrial dynamics hold potential for improving energy production and reducing oxidative stress in HF. Excessive ECM deposition and fibrosis contribute to cardiac dysfunction in HF. Therapies targeting ECM-modulating enzymes, such as matrix metalloproteinases and tissue inhibitors of metalloproteinases, aim to prevent fibrosis and preserve cardiac structure and function. Beyond traditional targets like the RAAS and β-adrenergic system, novel approaches aim to modulate other neurohormonal pathways involved in HF, such as the endothelin and natriuretic peptide systems, to improve hemodynamics and reduce symptoms. These novel therapeutic targets represent areas of active research in HF and hold promise for improving outcomes in patients with this debilitating condition. Further preclinical and clinical studies are needed to validate their efficacy, safety, and clinical utility [6].

Preclinical studies have yielded important insights into the efficacy and safety of novel therapeutic targets for HF. For example, studies using genetically modified animal models have elucidated the role of specific genes and signaling pathways in HF pathogenesis. Additionally, pharmacological interventions targeting these pathways have shown promising results in improving cardiac function, reducing fibrosis, and mitigating adverse remodeling in preclinical models. While preclinical studies offer valuable insights, there are several challenges and considerations in translating findings to clinical practice. Variability in disease models, differences in species biology, and limitations of in vitro assays can affect the predictive value of preclinical studies. Moreover, the complexity of HF pathophysiology and the heterogeneity of patient populations pose challenges in identifying optimal therapeutic targets and patient stratification strategies.

Moving forward, efforts should focus on enhancing the translational relevance of preclinical models, improving study design and methodology, and addressing key challenges in clinical translation. Collaborative approaches involving academia, industry, and regulatory agencies are essential for advancing novel therapies for HF. Moreover, innovative strategies such as precision medicine and the use of patient-derived models may help personalize treatment approaches and improve outcomes for HF patients.

Conclusion

Preclinical models are indispensable tools for evaluating novel therapeutic targets for heart failure. Insights gained from these studies have the potential to transform our understanding of HF pathophysiology and guide the development of more effective treatments. Despite challenges in translation, continued research efforts aimed at refining preclinical models and optimizing therapeutic strategies hold promise for improving outcomes in HF patients.

Acknowledgement

None.

Conflict of Interest

Authors declare no conflict of interest.

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